Alpha carbolines and uses thereof

ABSTRACT

This invention provides alpha-carboline compounds of formula I: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , R 3 , R 4 , R 5 , and x are as described in the specification. The compounds are useful for treating inflammatory diseases and cancer.

PRIORITY INFORMATION

The present application is a continuation of U.S. patent applicationSer. No. 11/706,760, filed Feb. 15, 2007 (pending), which claims thebenefit of U.S. Provisional Application Ser. No. 60/774,091, filed Feb.16, 2006 (abandoned). The entire contents of each of theabove-referenced patent applications are incorporated herein by thisreference.

BACKGROUND OF THE INVENTION

The transcription (nuclear) factor NF-κB is a member of the Rel proteinfamily, and is typically a heterodimer composed of p50 and p65 subunits.NF-κB is constitutively present in the cytosol, and is inactivated byits association with one of the IκB family of inhibitors. Palombella etal., WO 95/25533, teaches that the ubiquitin-proteasome pathway plays anessential role in the regulation of NF-κB activity, being responsiblefor the processing of p105 to p50 and the degradation of the inhibitorprotein IκB-α. Chen et al., Cell 84:853 (1996), teaches that prior todegradation, IκB-α undergoes selective phosphorylation at serineresidues 32 and 36 by the multisubunit IκB kinase complex (IKK). IκB-αis phosphorylated by IKK, which has two catalytic subunits, IKK-1 (IκBkinase α or IKK-α) and IKK-2 (IκB kinase β or IKK-β). Oncephosphorylated, IκB is targeted for ubiquitination and degradation bythe 26S proteasome, allowing translocation of NF-κB into the nucleus,where it binds to specific DNA sequences in the promoters of targetgenes and stimulates their transcription. Inhibitors of IKK can blockthe phosphorylation of IκB and its further downstream effects,particularly those associated with NF-κB transcription factors.

The protein products of genes under the regulatory control of NF-κBinclude cytokines, chemokines, cell adhesion molecules, and proteinsmediating cellular growth and control. Importantly, many of theseproinflammatory proteins also are able to act, either in an autocrine orparacrine fashion, to further stimulate NF-κB activation. In addition,NF-κB plays a role in the growth of normal and malignant cells.Furthermore, NF-κB is a heterodimeric transcription factor which canactivate a large number of genes which code, inter alia, forproinflammatory cytokines such as IL-1, IL-2, TNFα or IL-6. NF-κB ispresent in the cytosol of cells, building a complex with its naturallyoccurring inhibitor IκB. The stimulation of cells, for example bycytokines, leads to the phosphorylation and subsequent proteolyticdegradation of IκB. This proteolytic degradation leads to the activationof NF-κB, which subsequently migrates into the nucleus of the cell andactivates a large number of proinflammatory genes.

It would be beneficial to provide novel IKK inhibitors that possess goodtherapeutic properties, especially for the treatment of cancer,inflammatory diseases and immune-related diseases.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description f Compoundsof the Invention

This invention provides compounds that are inhibitors of IKK-2, andaccordingly are useful for the treatment of cancer, inflammatorydiseases, and immune-related diseases. The compounds of this inventionare represented by formula I:

or a pharmaceutically acceptable salt thereof wherein,

R¹ is hydrogen, C₁-C₄aliphatic, —C(O)N(R^(1a))₂, —C(O)R^(1b), or—(CH₂)_(n)R^(1c),

-   -   wherein each occurrence of R^(1a) is independently hydrogen,        C(O)OR^(1d), or an optionally substituted group selected from        C₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or wherein two        occurrences of R^(1a) are taken together with a nitrogen atom to        which they are bound to form an optionally substituted        3-7-membered heterocyclyl ring;    -   R^(1b) is an optionally substituted group selected from        C₁-C₆aliphatic or phenyl;    -   R^(1c) is —N(R^(1a))₂, or an optionally substituted phenyl or        pyridyl group;    -   R^(1d) is C₁-C₆aliphatic; and    -   n is 1, 2, or 3;        R² is hydrogen or C₁-C₄aliphatic;        R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e),        wherein

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and

each R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or—V₂-T₂-R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and

R⁵ is —NR⁶R⁷ or —OH, wherein:

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic;

-   -   provided that the compound of formula I is other than:        -   a) 2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide;        -   b) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the            monohydrochloride thereof,        -   c) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxylic acid; or        -   d)            2-amino-9-(2,6-dichlorophenyl)-9H-Pyrido[2,3-b]indole-3-carboxamide.

In other embodiments, the compounds of this invention are represented byformula I-A:

or a pharmaceutically acceptable salt thereof wherein,

R¹ is hydrogen, C₁-C₄aliphatic, or —C(O)N(R^(1a))₂;

wherein each occurrence of R^(1a) is independently hydrogen orC₁-C₄aliphatic;

R² is hydrogen or C₁-C₄aliphatic;R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e), wherein

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3e),—N(R^(3a))₂, —OR^(3a), —S(O)₂R^(3e), —C(O)R^(3a), —C(O)OR^(3a),—C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a),—N(R′)SO₂R^(3e), —N(R′)C(O)OR^(3a), —N(R′)C(O)N(R^(3a))₂, or—N(R′)SO₂N(R^(3a))₂, or two occurrences of R^(3a) or R^(3c) areoptionally taken together with their intervening atom(s) to form anoptionally substituted fused ring selected from a 6-membered aryl, or a5-6-membered heteroaryl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, or 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; and

each R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or—V₂-T₂-R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic;

-   -   provided that the compound of formula I is other than:        -   a) 2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide; or        -   b) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the            monohydrochloride thereof.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated.

As described herein, compounds of the invention may be optionallysubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, means that a hydrogenradical of the designated moiety is replaced with the radical of aspecified substituent, provided that the substitution results in astable or chemically feasible compound. The term “substitutable”, whenused in reference to a designated atom, means that attached to the atomis a hydrogen radical, which hydrogen atom can be replaced with theradical of a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby this invention are preferably those that result in the formation ofstable or chemically feasible compounds.

A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40°, in the absence of moistureor other chemically reactive conditions, for at least a week, or acompound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient. The phrase “oneor more substituents”, as used herein, refers to a number ofsubstituents that equals from one to the maximum number of substituentspossible based on the number of available bonding sites, provided thatthe above conditions of stability and chemical feasibility are met.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

As used herein, “a 3-7-membered saturated, partially unsaturated, oraromatic monocyclic ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or an 8-10-membered partiallyunsaturated, or aromatic bicyclic ring system having 0-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur” includescycloaliphatic, heterocyclic, aryl and heteroaryl rings.

As used herein, the term “aromatic” includes aryl and heteroaryl groupsas described generally below and herein.

The term “aliphatic” or “aliphatic group”, as used herein, means anoptionally substituted straight-chain or branched C₁₋₁₂ hydrocarbon, ora cyclic C₁₋₁₂ hydrocarbon which is completely saturated or whichcontains one or more units of unsaturation, but which is not aromatic(also referred to herein as “carbocycle”, “cycloaliphatic”,“cycloalkyl”, or “cycloalkenyl”). For example, suitable aliphatic groupsinclude optionally substituted linear, branched or cyclic alkyl,alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified,in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4,1-3, or 1-2 carbon atoms.

The term “alkyl”, used alone or as part of a larger moiety, refers to anoptionally substituted straight or branched chain hydrocarbon grouphaving 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkenyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The term “alkynyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to anoptionally substituted saturated or partially unsaturated cyclicaliphatic ring system having from 3 to about 14 ring carbon atoms. Insome embodiments, the cycloaliphatic group is an optionally substitutedmonocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms.Cycloaliphatic groups include, without limitation, optionallysubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, or cyclooctadienyl. The terms terms “cycloaliphatic”,“carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also includeoptionally substituted bridged or fused bicyclic rings having 6-12,6-10, or 6-8 ring carbon atoms, wherein any individual ring in thebicyclic system has 3-8 ring carbon atoms.

The term “cycloalkyl” refers to an optionally substituted saturated ringsystem of about 3 to about 10 ring carbon atoms. Exemplary monocycliccycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

The term “cycloalkenyl” refers to an optionally substituted non-aromaticmonocyclic or multicyclic ring system containing at least onecarbon-carbon double bond and having about 3 to about 10 carbon atoms.Exemplary monocyclic cycloalkenyl rings include cyclopentenyl,cyclohexenyl, and cycloheptenyl.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro, including perfluorinated aliphatic groups. Examples offluoroaliphatic groups include, without limitation, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionallysubstituted C₆₋₁₄aromatic hydrocarbon moiety comprising one to threearomatic rings. Preferably, the aryl group is a C₆₋₁₀aryl group. Arylgroups include, without limitation, optionally substituted phenyl,naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein,also include groups in which an aryl ring is fused to one or morecycloaliphatic rings to form an optionally substituted cyclic structuresuch as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl”may be used interchangeably with the terms “aryl group”, “aryl ring”,and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ arylC₁₋₆alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. A heteroarylgroup may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, ortricyclic, more preferably mono- or bicyclic. The term “heteroatom”refers to nitrogen, oxygen, or sulfur, and includes any oxidized form ofnitrogen or sulfur, and any quaternized form of a basic nitrogen. Forexample, a nitrogen atom of a heteroaryl may be a basic nitrogen atomand may also be optionally oxidized to the corresponding N-oxide. When aheteroaryl is substituted by a hydroxy group, it also includes itscorresponding tautomer. The terms “heteroaryl” and “heteroar-”, as usedherein, also include groups in which a heteroaromatic ring is fused toone or more aryl, cycloaliphatic, or heterocycloaliphatic rings.Nonlimiting examples of heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 8-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted. Additionally, a heterocyclic ring alsoincludes groups in which the heterocyclic ring is fused to one or morearyl rings.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aromatic(e.g., aryl or heteroaryl) moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. An optionally substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms isoptionally replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group and also includethose described in the specification herein.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is interrupted by the functional group. Examplesof suitable “interrupting functional groups” are described in thespecification and claims herein.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above, areintended to be read from left to right, with a correspondingleft-to-right reading of the formula or structure in which the variableappears.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. In addition to the substituents defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group also include and are generally selected from -halo,—NO₂, —CN, —R⁺, —C(R⁺)═C(R⁺)₂, —C≡C—R⁺, —OR⁺, —SR^(o), —S(O)R^(o),—SO₂R^(o), —SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺,—NR⁺C(O)N(R⁺)₂, —NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—R^(o), —NR⁺CO₂R⁺, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —O—C(O)R⁺,—O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺, —C(S)R^(o), —CO₂R⁺, —C(O)—C(O)R⁺,—C(O)N(R⁺)₂, —C(S)N(R⁺)₂, —C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺,—N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺, —C(R^(o))═N—OR⁺, —P(O)(R⁺)₂,—P(O)(OR⁺)₂, —O—P(O)—OR⁺, and —P(O)(NR⁺)—N(R⁺)₂, wherein R⁺,independently, is hydrogen or an optionally substituted aliphatic, aryl,heteroaryl, cycloaliphatic, or heterocyclyl group, or two independentoccurrences of R⁺ are taken together with their intervening atom(s) toform an optionally substituted 5-7-membered aryl, heteroaryl,cycloaliphatic, or heterocyclyl ring. Each R^(o) is an optionallysubstituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclylgroup.

An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic orheterocyclic ring may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclicring are selected from those listed above for the unsaturated carbon ofan aryl or heteroaryl group and additionally include the following: ═O,═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(o)═N—NHSO₂R^(o)or ═N—R* where R^(o) is defined above, and each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphaticgroup.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. Aring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ringalso may be oxidized to form the corresponding N-hydroxy or N-oxidecompound. A nonlimiting example of such a heteroaryl having an oxidizedring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences ofR⁺ (or any other variable similarly defined in the specification andclaims herein), are taken together with their intervening atom(s) toform a monocyclic or bicyclic ring selected from 3-13-memberedcycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R⁺(or any other variable similarly defined in the specification and claimsherein), are taken together with their intervening atom(s) include, butare not limited to the following: a) two independent occurrences of R⁺(or any other variable similarly defined in the specification or claimsherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R⁺)₂, where both occurrences of R⁺are taken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R⁺ (or any other variable similarly defined in thespecification or claims herein) that are bound to different atoms andare taken together with both of those atoms to form a ring, for examplewhere a phenyl group is substituted with two occurrences of OR⁺

these two occurrences of R⁺ are taken together with the oxygen atoms towhich they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings (e.g., Spiro andbridged rings) can be formed when two independent occurrences of R⁺ (orany other variable similarly defined in the specification and claimsherein) are taken together with their intervening atom(s) and that theexamples detailed above are not intended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

It is to be understood that, when a disclosed compound has at least onechiral center, the present invention encompasses one enantiomer ofinhibitor free from the corresponding optical isomer, racemic mixture ofthe inhibitor and mixtures enriched in one enantiomer relative to itscorresponding optical isomer. When a mixture is enriched in oneenantiomer relative to its optical isomers, the mixture contains, forexample, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or99.5%.

The enantiomers of the present invention may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. Where the desired enantiomer isconverted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the presentinvention encompasses a diastereomer free of other diastereomers, a pairof diastereomers free from other diasteromeric pairs, mixtures ofdiasteromers, mixtures of diasteromeric pairs, mixtures of diasteromersin which one diastereomer is enriched relative to the otherdiastereomer(s) and mixtures of diasteromeric pairs in which onediastereomeric pair is enriched relative to the other diastereomericpair(s). When a mixture is enriched in one diastereomer ordiastereomeric pair(s) relative to the other diastereomers ordiastereomeric pair(s), the mixture is enriched with the depicted orreferenced diastereomer or diastereomeric pair(s) relative to otherdiastereomers or diastereomeric pair(s) for the compound, for example,by a molar excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.

The diastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Specific procedures for chromatographically separatingdiastereomeric pairs of precursors used in the preparation of compoundsdisclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

In certain embodiments, for compounds of formula I or I-A, R⁵ is —NR⁶R⁷,and R⁶ and R⁷ are each hydrogen. In other embodiments, R⁶ and R⁷ areeach hydrogen, R¹ is hydrogen or —C(O)N(R^(1a))₂ and R² is hydrogen. Instill other embodiments, R¹, R², R⁶ and R⁷ are each hydrogen andcompounds have the structure of formula I-B:

In other embodiments, R³ is -T₁-R^(3d), —V₁-T₁-R^(3d), or —R^(3e). Inyet other embodiments, R³ is -T₁-R^(3d) or —V₁-T₁-R^(3d). In still otherembodiments, R³ is -T₁-R^(3d).

In some embodiments, T₁ is a C₁-C₄alkylene chain wherein the alkylenechain is optionally substituted by 1 or 2 independent occurrences ofR^(3b), and the alkylene chain is optionally interrupted by—C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—, andwherein each occurrence of R^(3b) is independently C₁-C₃aliphatic, —CN,—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂.

In other embodiments, T₁ is a C₁-C₄alkylene chain wherein the alkylenechain is optionally substituted by 1 or 2 independent occurrences ofR^(3b), and the alkylene chain is optionally interrupted by—C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—, andwherein each occurrence of —R^(3b) is independently C₁-C₃aliphatic,—N(R^(3a))₂, —OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂.

In some embodiments, R^(3d) is hydrogen. In other embodiments, eachoccurrence of R^(3b) is independently —N(R^(3a))₂, C₁-C₃alkyl, or—OR^(3a).

In other embodiments, x is 0, 1, or 2, and each occurrence of R⁴ isindependently halogen, CN, —NO₂, —R^(4c), —N(R^(4b))₂, —OR^(4b),—S(O)₂R^(4c), —C(O)R^(4b), —C(O)OR^(4b), —C(O)N(R^(4b))₂,—S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or —N(R′)SO₂R^(4c). In otherembodiments, each occurrence of R⁴ is independently halogen, —R^(4c),—N(R^(4b))₂, —OR^(4b), or —SR^(4c). In still other embodiments, eachoccurrence of R⁴ is independently halogen or C₁-C₄alkyl.

In still other embodiments, compounds have the structure of formula I-B:

wherein R³ is -T₁-R^(3d),

-   -   T₁ is a C₁-C₄alkylene chain wherein the alkylene chain is        optionally substituted by 1 or 2 independent occurrences of        R^(3b), and the alkylene chain is optionally interrupted by        —C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′ C(O)N(R′)—, —N(R′)S(O)₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—;    -   R^(3d) is hydrogen;

each occurrence of R^(3b) is independently C₁-C₃aliphatic, —N(R^(3a))₂,—OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂—N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂;

x is 0, 1, or 2; and

each occurrence of R⁴ is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or—N(R′)SO₂R^(4c).

In some embodiments, for compounds of formula I-B described directlyabove, T₁ is C₁-C₄alkyl substituted with 1 or 2 independent occurrencesof —R^(3b), wherein each occurrence of —R^(3b) is independently—N(R^(3a))₂, —OR^(3a), or C₁-C₃alkyl.

Table 1 below depicts certain exemplary compounds of formula I.

TABLE 1 Examples of formula I compounds

2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-9-methyl-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-6-chloro-9-ethyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-ethyl-6-methyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9H-pyrido[2,3-b]indole-3- carboxamide

9-acetyl-2-amino-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-9-isobutyryl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-benzoyl-9H-pyrido[2,3-b]indole- 3-carboxamide

2-amino-9-(2-hydroxyethyl)-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-(2-amino-2-oxoethyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[(2-methylpyridin-3-yl)-carbonyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(3-hydroxypropyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-isopropyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-propyl-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-9-(3-aminopropyl)-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-(2-aminoethyl)-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-[(dimethylamino)sulfonyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[2-(dimethylamino)ethyl]-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(2-morpholin-4-ylethyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[2-(1H-pyrrol-1-yl)ethyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-[(aminocarbonyl)amino]-9-ethyl-9H- pyrido[2,3-b]indole-3-carboxamide

9-[2-(acetylamino)ethyl]-2-amino-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-{2-[benzyl(methyl)amino]ethyl}-9H-pyrido[2,3-b]indole-3-carboxamide

tert-butyl {2-[2-amino-3-(aminocarbonyl)- 9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate

2-amino-9-(2-aminopropyl)-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-[2-(methylamino)ethyl]-9H- pyrido[2,3-b]indole-3-carboxamide

tert-butyl {2-[2-amino-3-(aminocarbonyl)- 9H-pyrido[2,3-b]indol-9-yl]-2-oxoethyl}carbamate

2-amino-9-[(benzyloxy)acetyl]-9H- pyrido[2,3-b]indole-3-carboxamide

tert-butyl {2-[2-amino-3-(aminocarbonyl)- 9H-pyrido[2,3-b]indol-9-yl]propyl}carbamate

2-amino-9-[(2S)-2-aminopropyl]-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(2-amino-1-methylethyl-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(1,4,5,6-tetrahydropyrimidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-6-bromo-9-ethyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-6-bromo-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-9-[(2R)-2-aminopropyl]-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(cyanomethyl)-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-(1H-imidazol-5-ylmethyl))-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(1H-imidazol-2-ylmethyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(2-aminobutyl)-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-(pyrrolidin-2-ylmethyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(2-amino-3-methylbutyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(2-amino-2-iminoethyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(2-hydroxy-2-methylpropyl)-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-isobutyl-9H-pyrido[2,3-b]indole- 3-carboxamide

9-[(2S)-2-aminopropyl]-2-(methylamino)-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-7-chloro-9-ethyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-(2-amino-2-methylpropyl)-9H- pyrido[2,3-b]indole-3-carboxamide

9-ethyl-2-(methylamino)-9H-pyrido[2,3- b]indole-3-carboxamide

2-(acetylamino)-9-ethyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-azetidin-3-yl-9H-pyrido[2,3- b]indole-3-carboxamide

9-[(2S)-2-aminopropyl]-2-(ethylamino)-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[(2S)-2-amino-1-methylpropyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[(2R)-2-hydroxycyclopentyl]-9H-pyrido[2,3-b]indole-3-carboxamide

9-[(2S)-2-aminopropyl]-2-(benzylamino)-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-5-chloro-9-ethyl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-{2-[(chloroacetyl)amino]-2-methylpropyl}-9H-pyrido[2,3-b]indole-3- carboxamide

2-amino-9-(2-hydroxypropyl)-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[2-(dimethylamino)-2- iminoethyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(4,5-dihydro-1H-imidazol-2-ylmethyl)-9H-pyrido[2,3-b]indole-3- carboxamide

9-[(2S)-2-aminopropyl]-2-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[(2R)-2-amino-3- (benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-6,7-difluoro-9H-pyrido[2,3- b]indole-3-carboxamide

tert-butyl (1-{[2-amino-3-(aminocarbonyl)- 9H-pyrido[2,3-b]indol-9-yl]methyl}cyclopropyl)carbamate

2-amino-9-[(1-aminocyclopropyl)methyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-[(2R)-2-amino-3-hydroxypropyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-(acetylamino)-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-pyridin-3-yl-9H-pyrido[2,3- b]indole-3-carboxamide

2-amino-9-phenyl-9H-pyrido[2,3-b]indole-3- carboxamide

tert-butyl (2-{[3-(aminocarbonyl)-9-ethyl- 9H-pyrido[2,3-b]indol-2-yl]amino}ethyl)carbamate

2-[(2-aminoethyl)amino]-9-ethyl-9H- pyrido[2,3-b]indole-3-carboxamide

2-amino-9-((2S)-2- {[amino(imino)methyl]amino}propyl)-9H-pyrido[2,3-b]indole-3-carboxamide

2-amino-9-(4-amino-2-hydroxycyclopentyl)-9H-pyrido[2,3-b]indole-3carboxamide

2-amino-9-{2-amino-1- [(benzyloxy)methyl]ethyl}-9H-pyrido[2,3-b]indole-3-carboxamide

4. General Synthetic Methods and Intermediates

The compounds of this invention may be prepared in general by methodsillustrated by the general schemes and by the preparative examples thatare described in the Experimental Procedures herein. Scheme I, as shownin the Experimental Procedures, depicts the general synthesis ofcompounds of formula I from the 2-cyanoacrylamide intermediate. SchemesII-VI more particularly depict the synthesis of certain exemplarycompounds of the invention.

Accordingly, in another aspect of the invention, a process for thesynthesis of compounds of formula I is provided:

or a pharmaceutically acceptable salt thereof wherein,

R¹ is hydrogen, C₁-C₄aliphatic, —C(O)N(R^(1a))₂, —C(O)R^(1b), or—(CH₂)_(n)R^(1c),

-   -   wherein each occurrence of R^(1a) is independently hydrogen,        C(O)OR^(1d), or an optionally substituted group selected from        C₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or wherein two        occurrences of R^(1a) are taken together with a nitrogen atom to        which they are bound to form an optionally substituted        3-7-membered heterocyclyl ring;    -   R^(1b) is an optionally substituted group selected from        C₁-C₆aliphatic or phenyl;    -   R^(1c) is —N(R^(1a))₂, or an optionally substituted phenyl or        pyridyl group;    -   R^(1d) is C₁-C₆aliphatic; and    -   n is 1, 2 or 3;        R² is hydrogen or C₁-C₄aliphatic;        R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e),        wherein

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and

each R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d),—V₂-T₂-R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and

R⁵ is —NR⁶R⁷ or —OH, wherein:

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic;

-   -   provided that the compound of formula I is other than:        -   a) 2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide;        -   b) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the            monohydrochloride thereof,        -   c) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxylic acid; or        -   d)            2-amino-9-(2,6-dichlorophenyl)-9H-Pyrido[2,3-b]indole-3-carboxamide,    -   wherein the process comprises contacting an intermediate of        formula II with an amine        NHR¹R² under suitable reaction conditions, wherein:    -   R¹ is hydrogen, C₁-C₄aliphatic, —C(O)N(R^(1a))₂, —C(O)R^(1b), or        —(CH₂)_(n)R^(1c),        -   wherein each occurrence of R^(1a) is independently hydrogen,            C(O)OR^(1d), or an optionally substituted group selected            from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,            3-10-membered heterocyclyl having 1-5 heteroatoms            independently selected from nitrogen, oxygen, or sulfur,            6-10-membered aryl, or 5-10-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur, or wherein two occurrences of R^(1a) are taken            together with a nitrogen atom to which they are bound to            form an optionally substituted 3-7-membered heterocyclyl            ring;        -   R^(1b) is an optionally substituted group selected from            C₁-C₆aliphatic or phenyl;        -   R^(1c) is —N(R^(1a))₂, or an optionally substituted phenyl            or pyridyl group;        -   R^(1d) it is C₁-C₆aliphatic; and        -   n is 1, 2, or 3;            R² is hydrogen or C₁-C₄aliphatic; and

the intermediate of formula II has the structure:

wherein:R³ is —H, -T₁-R^(3d), —V₁-T₁-R^(3d), or —R^(3c), wherein

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and

each R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or—V₂-T₂-R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—;

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring;

R⁵ is —NR⁶R⁷ or —OH, wherein:

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic; and

R⁸ is C₁-C₄alkyl;

provided that the intermediate of formula II is other than:

a) 2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide,

b) 2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide, or

c)2-cyano-3-[1-(2,6-dichlorophenyl)-2-ethoxy-1H-indol-3-yl]-2-Propenamide.

In yet another aspect of the invention, a process for the synthesis ofcompounds of formula I-A is provided:

wherein:R¹ is hydrogen or C₁-C₄aliphatic;R² is hydrogen or C₁-C₄aliphatic;R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e), wherein

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of —R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, or 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; and

each R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or—V₂-T₂-R^(4d), wherein:

each occurrence of —R^(4a) is independently halogen, —CN, —NO₂, —R^(4e),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO²N(R^(4b))², or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic;

provided that the compound of formula I is other than:

-   -   a) 2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide; or    -   b) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the        monohydrochloride thereof,    -   wherein the process comprises contacting an intermediate of        formula II-A with an amine NHR¹R² under suitable reaction        conditions, wherein:

R¹ is hydrogen, or C₁-C₄aliphatic, and each occurrence of R^(h) isindependently hydrogen or C₁-C₄aliphatic;

R² is hydrogen or C₁-C₄aliphatic; and

the intermediate of formula II-A has the structure:

wherein:

R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e), and

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or two occurrences ofR^(1a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; and

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, or 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur;

each —R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or—V₂-T₂R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—;

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring;

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic; andR⁸ is C₁-C₄alkyl;

provided that the intermediate of formula II-A is other than:

a) 2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide, or

b) 2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide.

In some embodiments for the process described directly above:

R¹ and R² are each hydrogen;

R³ is -T₁-R^(3d),

-   -   T₁ is a C₁-C₄alkylene chain wherein the alkylene chain is        optionally substituted by 1 or 2 independent occurrences of        —R^(3b), and the alkylene chain is optionally interrupted by        —C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—;    -   R^(3d) is hydrogen;

each occurrence of R^(3b) is independently —C₁-C₃aliphatic, —N(R^(3a))₂,—OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂;

x is 0, 1, or 2; and

each occurrence of R⁴ is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or—N(R′)SO₂R^(4c).

In other embodiments for the process described above, R⁴ is halogen or—C₁-C₃alkyl.

In still other embodiments for the process described above, T₁ isC₁-C₄alkyl substituted with 1 or 2 independent occurrences of —R^(3b),wherein each occurrence of —R^(3b) is independently —N(R^(3a))₂,—OR^(3a), or —C₁-C₃alkyl.

In yet another aspect of the invention, an intermediate of formula II isprovided:

wherein:R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e), wherein

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

heteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and

each R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or—V₂-T₂-R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4c) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—;

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring;

R⁵ is —NR⁶R⁷ or —OH, wherein:

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic; and

R⁸ is C₁-C₄alkyl;

provided that the intermediate of formula II is other than:

a) 2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide,

b) 2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide, or

c)2-cyano-3-[1-(2,6-dichlorophenyl)-2-ethoxy-1H-indol-3-yl]-2-Propenamide.

In still another aspect of the invention, an intermediate of formulaII-A is provided:

wherein:

R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e), and

V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—;

T₁ is a C₁-C₆alkylene chain optionally substituted with one or moreindependent occurrences of —R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring;

each occurrence of R^(3a) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring;

each occurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or two occurrences ofR^(1a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; and

each occurrence of R^(3e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, or 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur;

each —R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic;

x is 0-4;each occurrence of R⁴ is independently —R^(4a), -T₂-R^(4d),—V₂-T₂-R^(4d), wherein:

each occurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur;

each occurrence of R^(4b) is independently hydrogen or an optionallysubstituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

each occurrence of R^(4b) is independently an optionally substitutedgroup selected from C₁-C₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of V₂ is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—;

each occurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring;

R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic; andR⁸ is C₁-C₄alkyl;

provided that the intermediate of formula II-A is other than:

a) 2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide, or

b) 2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide.

In some embodiments, for the intermediate of formula II-A:

R³ is -T₁-R^(3d),

-   -   T₁ is a C₁-C₄alkylene chain wherein the alkylene chain is        optionally substituted by 1 or 2 independent occurrences of        —R^(3b), and the alkylene chain is optionally interrupted by        —C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R⁹)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—;    -   R^(3d) is hydrogen;

each occurrence of —R^(3b) is independently C₁-C₃aliphatic, —N(R^(3a))₂,—OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂;

x is 0, 1, or 2; and

each occurrence of R⁴ is independently halogen, —CN, —NO₂, —N(R^(4b))₂,—OR^(4b), —SR^(4c), —S(O)₂R^(4c), —X(O)R^(4b), —C(O)OR^(4b),—C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or —N(R′)SO₂R^(4c).

In yet other embodiments, for the intermediate of formula II-A, T₁ isC₁-C₄alkyl substituted with 1 or 2 independent occurrences of R^(3b),wherein each occurrence of R^(3b) is independently —N(R^(3a))₂,—OR^(3a), or —C₁-C₃alkyl.

5. Uses, Formulation and Administration

As discussed above, the present invention provides compounds that areuseful as inhibitors of IKK, and thus the present compounds are usefulfor treating or lessening the severity of cancer, an inflammatorydisease, or an immune-related disease including, but not limited to,lymphoma, such as diffuse large B-cell, primary mediastinal B-cell, andmantle cell; multiple myeloma; osteolytic bone metastasis; head and necksquamous cell cancer; prostate cancer; pancreatic cancer, non-small celllung cancer, joint inflammation (e.g., rheumatoid arthritis (RA),rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubellaarthritis, psoriatic arthritis, osteoarthritis, and other arthriticconditions), acute synovitis, tuberculosis, atherosclerosis, muscledegeneration, cachexia, Reiter's syndrome, endotoxaemia, sepsis, septicshock, endotoxic shock, gram negative sepsis, gout, toxic shocksyndrome, pulmonary inflammatory diseases (e.g., asthma, acuterespiratory distress syndrome, chronic obstructive pulmonary disease,silicosis, pulmonary sarcoidosis, and the like), bone resorptiondiseases, reperfusion injuries, carcinoses, leukemia, sarcomas, lymphnode tumors, skin carcinoses, lymphoma, apoptosis, graft versus hostreaction, graft versus host disease (GVHD), allograft rejection,leprosy, viral infections (e.g., HIV, cytomegalovirus (CMV), influenza,adenovirus, the Herpes group of viruses, and the like), parasiticinfections (e.g., malaria, such as cerebral malaria), yeast and fungalinfections (e.g., fungal meningitis), fever and myalgias due toinfection, acquired immune deficiency syndrome (AIDS), AIDS relatedcomplex (ARC), cachexia secondary to infection or malignancy, cachexiasecondary to AIDS or cancer, keloid and scar tissue formation, pyresis,diabetes, inflammatory bowel diseases (IBD) (e.g., Crohn's disease andulcerative colitis), multiple sclerosis (MS), ischemic brain injury,e.g. cerebral infarction (stroke), head trauma, psoriasis, Alzheimer'sdisease, carcinomatous disorders (potentiation of cytotoxic therapies),cardiac infarct, chronic obstructive pulmonary disease (COPD), and acuterespiratory distress syndrome (ARDS).

It will also be appreciated that the present compounds are useful fortreating diseases, disorders or symptoms related to the activity ofNF-κB, TNF-α, and other enzymes in pathways where IKK is known tomodulate activity.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, wherein these compositions comprise any ofthe compounds as described herein, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of IKK.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preseryatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, a method for treating cancer is providedcomprising administering an effective amount of a compound, or apharmaceutical composition to a subject in need thereof. In yet anotheraspect, a method for treating an inflammatory disease or immune-relateddisease is provided comprising administering an effective amount of acompound, or a pharmaceutical composition to a subject in need thereof.In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutical composition is that amount effective fortreating cancer, or is that amount effective for treating aninflammatory disease or immune-related disease. In other embodiments, an“effective amount” of a compound is an amount which inhibits binding ofIKK and thereby blocks the phosphorylation of IKB and its furtherdownstream effects.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating the disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disease beingtreated and the severity of the disease; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described above, compounds of the invention are inhibitors of IKK.Accordingly, compounds of the invention are suitable for the prophylaxistreatment and therapy of diseases, disorders and symptoms that involveincreased activity of IkB kinase. These include, for example, jointinflammation (e.g., rheumatoid arthritis (RA), rheumatoid spondylitis,gouty arthritis, traumatic arthritis, rubella arthritis, psoriaticarthritis, osteoarthritis, and other arthritic conditions), acutesynovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia,Reiter's syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock,gram negative sepsis, gout, toxic shock syndrome, pulmonary inflammatorydiseases (e.g., asthma, acute respiratory distress syndrome, chronicobstructive pulmonary disease, silicosis, pulmonary sarcoidosis, and thelike), bone resorption diseases, reperfusion injuries, carcinoses,leukemia, sarcomas, lymph node tumors, skin carcinoses, lymphoma,apoptosis, graft versus host reaction, graft versus host disease (GVHD),allograft rejection and leprosy.

Furthermore, the inventive compounds may be used in the treatment ofimmune-related diseases, symptoms and disorders, for example,infections, such as viral infections (e.g., HIV, cytomegalovirus (CMV),influenza, adenovirus, the Herpes group of viruses, and the like),parasitic infections (e.g., malaria, such as cerebral malaria), andyeast and fungal infections (e.g., fungal meningitis). In addition, theinventive compounds can be useful for treating fever and myalgias due toinfection, acquired immune deficiency syndrome (AIDS), AIDS relatedcomplex (ARC), cachexia secondary to infection or malignancy, cachexiasecondary to AIDS or cancer, keloid and scar tissue formation, pyresis,diabetes, and inflammatory bowel diseases (IBD) (e.g., Crohn's diseaseand ulcerative colitis). The compounds of the invention are also usefulin the treatment of diseases or injuries to the brain in whichover-expression of TNF-α has been implicated, such as multiple sclerosis(MS), ischemic brain injury, e.g. cerebral infarction (stroke) and headtrauma. The compounds of the invention are also useful in the treatmentof psoriasis, Alzheimer's disease, carcinomatous disorders (potentiationof cytotoxic therapies), cardiac infarct, chronic obstructive pulmonarydisease (COPD) and acute respiratory distress syndrome (ARDS).

In some embodiments, the compounds of formula (I) are useful fortreating inflammatory and immune-related diseases, disorders andsymptoms, more especially, inflammatory ones such as RA, asthma, IBD,psoriasis, COPD and MS.

In other embodiments, compounds of the invention are useful for treatingcancer, especially for treating cancers where IKK activity is abnormallyhigh. The cancer types that may be treated include lymphoma, such asdiffuse large B-cell (Davis, et al., J. Exp. Med. 2001, 194, 1861-1874;Lam et al., Clin. Cancer Res. 2005, 11, 28-40; Feuerhake et al., Blood,2005, 106, 1392-1399), primary mediastinal B-cell, and mantle cell;multiple myeloma (Berenson et al., Clin. Adv. Hematol. Oncol. 2004, 2,162-166; Gunn et al., Stem Cells, 2005); osteolytic bone metastasis(Ruocco et al., J. Exp. Med. 2005, 201, 1677-1687; Morony, et al.,Endocrinology, 2005, 146, 3235-3243; Gordon, et al., Cancer Res., 2005,65, 3209-3217; RoleSohara, et al., Cancer Lett., 2005, 228, 203-209);head and neck squamous cell cancer (van Hogerlinden et al., J. Invest.Dermatol., 2004, 123 101-108; Tamatani et al, Int. J. Cancer., 2004,108, 912-921; Loercher et al., Cancer Res. 2004, 64, 6511-6523; Van Waeset al., Int. J. Radiat. Oncol. Biol. Phys. 2005 63, 1400-1412); prostatecancer; pancreatic cancer and non-small cell lung cancer. In oneembodiment, the compounds are useful for ABC lymphoma.

The compounds of this invention are also useful for treating a boneassociated disease, symptom or disorder in which there is a deficit ordeficiency of bone—either as a result of decreased new bone formation oran increase in bone resorption or a combination of both. Specificexamples include osteoporosis, periodontal disease, osteomyelitis,rheumatoid arthritis, aseptic joint loosening and osteolytic lesions(typically cancer related). It is known that rheumatoid arthritis, whichis characterized by inflammation of the joints, is also associated withdestruction of cartilage and bone. Furthermore, it has been reportedthat an IKK inhibitor provided inhibition of cartilage and bone loss ina murine model of collagen-induced arthritis. See McIntyre et al.,Arthritis & Rheumatism (2003), 48(9), 2652-2659.

Osteoporosis is a broad term applied to a number of distinct diseases inwhich there is decreased bone mass. These include primary osteoporosis(e.g., post-menopausal, senile osteoporosis and juvenile osteoporosis)and secondary osteoporosis. Examples of secondary osteoporosis would bethose associated with chronic diseases (e.g., chronic renal disease,hepatic insufficiency, gastrointestinal malabsorption, chronicimmobilization and chronic inflammatory diseases, including rheumatoidarthritis, osteoarthritis, periodontal disease and aseptic prostheticjoint loosening), endocrine dysfunction related diseases (e.g.,diabetes, hyperthyroidism, hyperparathyroidism, hypogonadism andhypopituitarism), drug and substance related symptoms (e.g.,corticosteroid, heparin, anticonvulsants, alcohol andimmunosupressants), and hematological disorders (e.g., metastaticdisease, myeloma, leukemia, gaucher's disease and anemia). Inhibition ofeither IkB directly or the NF-kB pathway indirectly has been reported tobe useful for the treatment of osteoporosis and osteoarthritis. See, forexample, PCT applications WO 2003104219, WO 2003103658, WO 2003029242,WO 2003065972, and WO 9965495. Accordingly, this invention also providesa method of treating or preventing bone loss in a patient in needthereof, comprising administering to the patient a compound of thisinvention. Also provided is a method of generating bone formation in apatient comprising administering a compound of this invention.

Another embodiment of the invention provides a method of inhibitingactivation of NF-κB dependent gene expression associated with theinhibition of IKK catalytic activity and/or IκB phosphorylation,comprising administering to a patient in need thereof an amount of acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof, which iseffective to inhibit IKK catalytic activity and/or IκB phosphorylation,thereby inhibiting activation of NF-κB dependent gene expression.

In one embodiment of the invention, there is provided a method oftreating an inflammatory or immune-related disease in a patient in needof such treatment, comprising administering to the patient an amount ofat least one compound of the invention, or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition thereof, whichis effective to treat the inflammatory or immune-disease. Preferably,the inflammatory disease, disorder or symptom is rheumatoid arthritis,asthma, psoriasis, psoriatic arthritis, chronic obstructive pulmonarydisease (COPD), inflammatory bowel disease or multiple sclerosis.

In another embodiment, there is provided a method of treating cancercomprising administering to the patient an amount of at least onecompound of the invention, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof, which iseffective to treat the cancer. In certain embodiments, the cancer is alymphoma (more preferably non-Hodgkin's lymphoma), multiple myeloma, orhead and neck squamous cell carcinoma.

In yet another embodiment of the invention, there is provided a methodof treating cystic fibrosis in a patient in need of such treatment,comprising administering to the patient an amount of at least onecompound of the invention, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof.

While one or more of the inventive compounds may be used in anapplication of monotherapy to treat a disorder, disease or symptom, theyalso may be used in combination therapy, in which the use of aninventive compound or composition (therapeutic agent) is combined withthe use of one or more other therapeutic agents for treating the sameand/or other types of disorders, symptoms and diseases. Combinationtherapy includes administration of the therapeutic agents concurrentlyor sequentially. Alternatively, the therapeutic agents can be combinedinto one composition which is administered to the patient.

In one embodiment, the compounds of this invention are used incombination with other therapeutic agents, such as other inhibitors ofIKK, other agents useful in treating NF-κB and TNF-α associatedconditions, and agents useful for treating other disorders, symptoms anddiseases. In particular, agents that induce apoptosis such as agentsthat disrupt cell cycle or mitochondrial function are useful incombination with the IKK inhibitors of this invention. Exemplary agentsfor combination with the IKK inhibitors include antiproliferative agents(e.g., methotrexate) and the agents disclosed in U.S. Pat. ApplicationPublication No. US2003/0022898, p 14, para. [0173-0174], which isincorporated herein in its entirety. In some embodiments, a compound ofthe invention is administered in conjunction with a therapeutic agentselected from the group consisting of cytotoxic agents, radiotherapy,and immunotherapy. Non-limiting examples of cytotoxic agents suitablefor use in combination with the IKK inhibitors of the invention includecapecitibine; gemcitabine; irinotecan; fludarabine; 5-fluorouracil or5-fluorouracil/leucovorin; taxanes, including, e.g., paclitaxel anddocetaxel; platinum agents, including, e.g., cisplatin, carboplatin, andoxaliplatin; anthracyclins, including, e.g., doxorubicin and pegylatedliposomal doxorubicin; mitoxantrone; dexamethasone; vincristine;etoposide; prednisone; thalidomide; herceptin; temozolomide; andalkylating agents such as melphalan, chlorambucil, and cyclophosphamide.It is understood that other combinations may be undertaken whileremaining within the scope of the invention.

Another aspect of the invention relates to inhibiting IKK, activity in abiological sample or a patient, which method comprises administering tothe patient, or contacting said biological sample with a compound offormula I or a composition comprising said compound. The term“biological sample”, as used herein, generally includes in vivo, invitro, and ex vivo materials, and also includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treatdisorders, symptoms and diseases where IkB kinase plays a role.

EXPERIMENTAL PROCEDURES

Unless otherwise stated, analytical LCMS conditions are as follows:

Standard Conditions Column type: Waters Symmetry C18 100×4.6 mm IC, 3.5μmRun time: 10.00 minute runQC Conditions Column type: Waters symmetry C18 50×4.6 mm ID, 3.5 μmRun time: 5.00 minute run

NH₄OAc (A) Standard Conditions: Solvent A: 10 mM NH₄Oac 98% H₂O 2%Isopropyl alcohol Solvent B: 10 mM NH₄Oac 25% Methanol 75% MeCN HCOOH(FA) Standard and QC Conditions: Solvent C: 0.1% HCOOH 99% H₂O 1% MeCNSolvent D: 0.1% HCOOH 5% H₂O 95% MeCN NH₄Oac (AA) QC conditions: SolventA: 10 mM NH₄Oac 99% H₂O 1% MeCN Solvent B: 10 mM NH₄OAc 5% H2O 95% MeCNTime [min] Solvent A % Solvent B % Flow rate [ml/min] Standard gradient(ammonium acetate and formic acid conditions): 0.00 95.0 5.0 1.0 7.500.0 100.0 1.0 8.00 0.0 100.0 1.0 9.75 0.0 100.0 1.0 9.80 95.0 5.0 1.010.00  95.0 5.0 1.0 QC gradient (ammonium acetate and formic acidconditions): 0.00 95.0 5.0 1.0 3.50 0.0 100.0 1.0 4.90 0.0 100.0 1.05.0  95.0 5.0 1.0

Example 1 Synthesis of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5)

The synthesis of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5) isexemplified generally in Scheme I and is described specifically below

Step 1: (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one(iii-a)

To a solution of 1,3-dihydro-2H-indol-2-one 25.0 g, 189 mmol) in CHCl₃(150 mL) was added N,N-dimethylformamide dimethyl acetal (29.2 mL, 209mmol) and the reaction was heated at 70° C. under an atmosphere ofargon. After 4.5 h, the reaction was cooled to RT and was concentrated.The resulting solid was triturated with ether and filtered to give(3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellowsolid (iii-a, 33.0 g, 93%). NH₄OAc QC conditions. DAD RetentionTime=1.19 min. M+H=189.

Step 2:(3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one(iv-a)

To a solution of(3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one (iii-a, 626mg, 3.33 mmol) in DMF (10 mL) was added Nail (151 mg, 6.29 mmol) and thereaction was stirred at RT. After 10 min, benzyl bromide (500 μL, 4.20mmol) was added and the mixture was stirred under an atmosphere of Arfor 22 h. The reaction was quenched with a few drops of water and pouredinto a separatory funnel containing EtOAc (150 mL) and was washed withwater (2×100 mL), followed by brine (100 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated. The crude productwas purified by silica gel chromatography (EtOAc/Hexane) to yield(3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one asa yellow solid (iv-a, 660 mg, 71%). N′H₄OAc QC conditions. DAD RetentionTime=1.71 min. M+H=279.

Step 3:N-[(1-benzyl-2-ethoxy-1H-indol-3-yl)methylene]-N-methylmethanaminiumtetrafluoroborate (v-a)

To a solution of(3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one(iv-a, 7.69 g, 27.6 mmol) in dichloroethane (50 mL) was addedtriethyloxonium tetrafluoroborate (10.7 g, 56.4 mmol) and the reactionmixture was heated at 110° C. under an atmosphere of Ar. After 3 h, thereaction was cooled to RT and was concentrated. The crude material wasstirred in ether (75 mL) and a solid was precipitated. The solid wasfiltered to yieldN-[(1-benzyl-2-ethoxy-1H-indol-3-yOmethylene]-N-methylmethanaminiumtetrafluoroborate (v-a, theoretical yield 27.6 mmol) as a brown solidwhich was used without further purification in the next step. NH₄OAc QCconditions. DAD Retention Time=1.28 min. M+H=308.

Step 4: (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide(vi-a)

To a mixture of cyanoacetamide (4.60 g, 54.7 mmol) and NaOMe (0.5 Msolution in MeOH, 80 mL, 4 mmol) was added a solution of(N-[(1-benzyl-2-ethoxy-1H-indol-3-yl)methylene]-N-methylmethanaminiumtetrafluoroborate (v-a, 27.6 mmol) in MeOH (120 mL). The reaction wasstirred at RT under an atmosphere of Ar. After 15 h, the reaction wascooled to 0° C. and was quenched by the addition of water. The insolubleproduct was filtered, triturated in MeOH and refiltered to yield ayellow solid (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide(vi-a, 5.68 g, 60%). NH₄OAc QC conditions. DAD Retention Time=1.78 min.M+H=346.

Step 5: 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide

To a solution of(2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide (vi-a, 2.00g, 5.79 mmol) in MeOH (150 mL) was added NH₄OH (30% weight solution ofNH₃ in water, 100 mL). The reaction was stirred at RT overnight. Thereaction was concentrated under reduced pressure and the crude solid wastriturated with H₂O. The solid was filtered and triturated again withether. A yellow solid was collected by suction filtration to yield2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide 1.23 g, 63%).NH₄OAc standard conditions. DAD Retention time=7.25 min. M+H=317. ¹H NMR(300 MHz, DMSO-d₆): δ 8.77 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.62 (br s,2H), 7.40 (d, J=7.7 Hz, 1H), 7.31-7.16 (m, 9H), 5.52 (s, 2H).

2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5)

To a solution of 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide(vii-a, 1.01 g, 319 mmol) in benzene (30 mL) was added AlCl₃ (1.10 g,8.25 mmol), and the reaction was heated to 95° C. under atmosphere ofAr. After 6 h, the reaction was cooled to 0° C., quenched with water (75mL) and poured into a separatory funnel containing EtOAc (200 mL). Themixture was washed with 1N NaOH (2×200 mL) and the organic layer wasdried over sodium sulfate, filtered and concentrated to yield2-amino-9H-pyrido[2,3-b]indole-3-carboxamide as a light brown solid (5,319 mg, 44%). NH₄OAc Standard conditions. DAD Retention Time=5.10 min.M+H=227. ¹H NMR (300 MHz, DMSO-d₆): δ 11.33 (br s, 1H), 8.68 (s, 1H),7.85 (br s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.44 (br s, 1H), 7.32 (d, J=7.3Hz, 1H), 7.24 (dd, J=7.3, 7.3 Hz, 1H), 7.12 (dd, J=7.9, 7.9 Hz, 1H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in example 1.

LCMS Standard No. Method: (FA/AA) ES+ ES− Retention Time (min) 5 AA 3755.10 62 AA (QC Conditions) 263 261 1.63 (QC Conditions) 1 AA 255 2537.89 2 AA 241 239 6.35 3 AA 287 289 7.52 46 AA 289 287 7.24 55 AA 289287 7.17

2-amino-6-bromo-9H-pyrido[2,3-b]indole-3-carboxamide (34)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 35 mg,0.15 mmol) in acetonitrile (1 mL) and N,N-dimethylformamide (1 mL), wasadded N-bromosuccinimide (37 mg, 0.209 mmol) in one portion at −10° C.The mixture was warmed to room temperature and stirred for one hour.Water was added and the mixture was extracted with methylene chloride(3×20 mL). Extracts were combined, dried over sodium sulfate, filteredand concetnrated to afford the crude product which was subsequentlypurified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH₃CN) toyield 2-amino-6-bromo-9H-pyrido[2,3-b]indole-3-carboxamide (34, 20 mg,40%) as yellow solid. NH₄OAc standard conditions. DAD RetentionTime=6.12 min. M+H=307. ¹H NMR (300 MHz, MeOD): δ 8.65 (d, J=6.9 Hz,1H), 8.03 (d, J=4.9 Hz, 1H), 7.43-7.37 (m, 1H), 7.33-7.27 (m, 1H).

2-amino-9-ethyl-6-methyl-9H-pyrido[2,3-b]indole-3-carboxamide (4)

2-Amino-9-ethyl-6-methyl-9H-pyrido[2,3-b]indole-3-carboxamide wasprepared from i-a (see Example 2 below) following the proceduresdetailed in example 1 as depicted in Scheme 1. NH₄OAc standardconditions. DAD R_(f)=7.33 min. M+H=268.

Example 2 Synthesis of 1-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one (i-a)

Step 1: 1-ethyl-5-methyl-1H-indole-2,3-dione (ix-a)

To a solution of 1-ethyl-5-methyl-1H-indole-2,3-dione (viii-a, 2.04 g,12.4 mmol) in DMF (50 mL) was added NaH (601 mg, 15.0 mmol). After 15min, C₂H₅I (1.20 mL, 15.0 mmol) was added. The reaction was stirred atRT for 3 h, quenched with water and poured into a reparatory funnelcontaining EtOAc (200 mL). The mixture was shaken and the layers wereseparated. The organic layer was washed with water (4×150 mL), dried,filtered and concentrated. The resulting solid was triturated in etherand was filtered to yield 1-ethyl-5-methyl-1H-indole-2,3-dione as abrick red solid (ix-a, 1.53 g, 66%). NH₄OAc QC conditions. DAD RetentionTime=1.50 min. M+H=191.

Step 2: 1-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one (i-a)

A mixture of 1-ethyl-5-methyl-1H-indole-2,3-dione (ix-a, 1.53 g, 8.09mmol) and hydrazine monohydrate (30 mL, 618 mmol) was heated to 110° C.After 5 h, the reaction was cooled to RT and conc. HCl was added toadjust the reaction mixture to approximately pH 3. The mixture wasstirred overnight, and poured into a separatory funnel containing EtOAc(150 mL). The mixture was shaken and the layers were separated. Theaqueous layer was extracted with EtOAc (2×150 mL) and the combinedorganic layers were dried, filtered and concentrated to give1-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one (i-a, 1.03 g, 72.5%). NH₄OAcQC conditions. DAD Retention time=1.48 min. M+H=176.

Example 3 Synthesis of Exemplary N-Substituted Alpha Carbolines

The examples below depict the synthesis of a variety of N-substitutedalpha carbolines from the general intermediate (xi).

2-amino-9-isopropyl-9H-pyrido[2,3-b]indole-3-carboxamide (13)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 122mg, 0.540 mmol) in DMF (5 mL) was added NaH (110 mg, 2.75 mmol) and thereaction was stirred for 10 min. 2-Bromopropane (111 μL, 0.688 mmol) wasadded and the mixture was stirred at RT for another 2.5 h. The reactionwas quenched with water (50 mL), poured into a separatory funnelcontaining EtOAc (150 mL), the mixture was shaken and the layers wereseparated. The organic layer was washed with brine (100 mL), dried,filtered and concentrated. The crude product was purified by silica gelchromatography (MeOH/CH₂Cl₂ gradient) to yield2-amino-9-isopropyl-9H-pyrido[2,3-b]indole-3-carboxamide as a whitepowder (13, 30 mg, 21%). NH₄OAc standard conditions. DAD Retentiontime=6.95 min. M+H=269. ¹H NMR (300 MHz, DMSO-d₆):

8.72 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (brs, 2H), 7.29 (ddd, J=8.4, 8.4, 1.2 Hz, 1H), 7.17 (ddd, J=7.5, 7.5, 0.9Hz, 1H), 5.23 (septet, J=6.9 Hz, 1H), 1.60 (d, J=6.9 Hz, 6H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 13.

LCMS Standard No. Method: (FA/AA) ES+ ES− Retention Time (min) 10 AA 284282 4.51 13 AA 269 6.95 14 AA 269 267 6.88 18 FA 298 296 3.54 33 AA 3337.36 36 AA 266 264 5.68 23 AA 374 7.81 24 FA 384 3.79 29 AA 384 382 6.97

2-amino-9-isobutyl-9H-pyrido[2,3-b]indole-3-carboxamide (44)

Step 1:2-amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide(xii-a)

2-Amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 196 mg, 0.866 mmol) wasalkylated with methallyl bromide (0.131 mL, 1.30 mmol) according to theprocedure detailed in the synthesis of 13 to afford2-amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide(xii-a, 143 mg, 59%).

Step 2: 2-amino-9-isobutyl-9H-pyrido[2,3-b]indole-3-carboxamide (44)

2-Amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide(xii-a, 143 mg) was dissolved in ethanol (40 mL) and placed under anargon atmosphere. 10% Palladium on carbon (26 mg) was added and thereaction placed under an atmosphere of hydrogen by repeated evacuationfollowed by back-filling using a balloon filled with hydrogen gas. Thereaction stirred for 16 h at room temperature then the catalyst wasremoved by filtration through Celite® and the filtrate concentrated invacuo. The residue was purified by silica gel chromatography (5%methanol in methylene chloride) to afford the title compound (44, 44 mg,65%). NH₄OAc standard conditions. DAD Retention time=7.45 min. M+H=283.¹H NMR (300 MHz, CDCl₃):

8.22 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.30-7.36 (m, 3H), 7.21 (br s,1H), 6.66 (br s, 1H), 5.67 (br s, 1H), 4.07 (d, J=7.3 Hz, 1H), 2.28-2.42(m, 1H), 0.94 (d, J=6.7 Hz, 6H).

2-amino-9-(1,4,5,6-tetrahydropyrimidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(32)

To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide(5, 100 mg, 0.44 mmol) in dimethyl sulfoxide (1 mL) was added powderedpotassium hydroxide (370 mg, 6.6 mmol), and the resulting mixturestirred at room temperature for 10 min.2-(Chloromethyl)-1,4,5,6-tetrahydropyrimidine.HCl (Stillings, M. R., J.Med. Chem. 1986, 29, 2280-2284; 220 mg, 1.3 mmol) in dimethyl sulfoxide(1 mL) was added dropwise to the mixture over 0.5 h at 5-10° C. Uponcompletion of addition, the reaction was allowed to stir overnight atroom temperature. The crude reaction mixture was concentrated underreduced pressure and purified by HPLC (Phenomenex Luna 15 μm C18,aqueous HCOOH/CH₃CN) to yield2-amino-9-(1,4,5,6-tetrahydropyrimidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(32, 14 mg, 10%). NH₄OAc standard conditions. DAD Retention time=4.42min. M+H=323. ¹H NMR (300 MHz, MeOD): δ 8.73 (s, 1H), 8.49 (s, 1H), 7.94(d, J=6.9 Hz, 1H), 7.42-7.40 (m, 2H), 7.33-7.27 (m, 1H), 5.29 (s, 2H),3.45 (t, J=5.7 Hz, 4H), 2.04 (t, J=5.7 Hz, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 32.

LCMS Standard No. Method: (FA/AA) ES+ ES− Retention Time (min) 38 AA 3075.03 37 AA 307 4.98 32 AA 323 4.42

tert-butyl(1-{[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]methyl}cyclopropyl)carbamate(63)

To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide(5, 318 mg, 1.41 mmol) in N,N-dimethylformamide (17 mL) was addedpowdered cesium carbonate (2.29 g, 7.03 mmol), tert-butyl[1-(iodomethyl)cyclopropyl]carbamate (2.26 g, 7.61 mmol, prepared fromthe corresponding alcohol (J. Med. Chem. 1988, 31, 1694-7) following theprocedure detailed in the preparation of xxvii below) was added. Themixture was heated at 100° C. under nitrogen for 2 h. The reaction wascooled to room temperature, diluted with ethyl acetate (150 mL) andwashed thrice with water and twice with brine. The extracts were driedover magnesium sulfate, filtered and concentrated. The crude product waspurified by silica gel chromatography (95/5 methylene chloride/methanolto 93/7 methylene chloride/methanol gradient) to afford the titledproduct (63, 75 mg, 13%). NH₄OAc Standard conditions. DAD Retentiontime=7.29 min. M+H=396. ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (s, 1H), 7.79(d, J=7.3 Hz, 1H), 7.54-7.41 (m, 2H), 7.26 (dd, J=7.3 Hz, 1H), 7.20-7.11(m, 2H), 4.34 (s, 2H), 1.35 (s, 9H), 1.18-1.05 (m, 2H), 0.65-0.54 (m,2H).

2-amino-9-pyridin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (67)

To a stirred mixture of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5,100 mg, 0.44 mmol), Copper(I) iodide (8 mg, 0.045 mmol) and potassiumphosphate (190 mg, 0.88 mmol) under dry nitrogen was added(±)-trans-1,2-diaminocyclohexane (5 μL, 0.04 m mol) and 3-bromopyridine(43 μL, 0.442 mmol), followed by 1,4-dioxane (2 mL). The mixture washeated at 110° C. for 2 days. The reaction mixture was cooled to roomtemperature, extracted with methylene chloride (3×30 ml) and washed withwater. The extracts were combined, dried over sodium sulfate, filteredand concentrated. The crude product was purified by silica gelchromatography (12 g silica, methylene chloride to 90/10 methylenechloride/methanol gradient) to yield2-amino-9-pyridin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (67, 20 mg,10%). NH₄OAc standard conditions. DAD Retention time=5.99 min. M+H=310.¹H NMR (300 MHz, MeOD): δ 8.86 (d, J=2.4 Hz, 1H), 8.74 (s, 1H),8.66-8.63 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.70(dd, J=4.7, 8.2 Hz, 1H), 7.36-7.28 (m, 4H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 67.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 67 AA 3045.99 68 AA 303 301 7.46

Example 222-amino-9-[2-(1H-pyrrol-1-yl)ethyl]-9H-pyrido[2,3-b]indole-3-carboxamide(20)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 70 mg,0.310 mmol) in DMF (2 mL) was added potassium tert-butoxide (84 mg,0.749 mmol). The reaction mixture was stirred at room temperature for 10min, then 1-(2-bromoethyl)-1H-pyrrole (162 mg, 0.930 mmol) and potassiumiodide (164 mg, 0.930 mmol) were added and the mixture was stirred atroom temperature overnight. The reaction was quenched with water (50 mL)and extracted with ethyl acetate (150 mL). The layers were separated andthe organic layer was washed with brine (100 mL), dried over magnesiumsulfate, filtered and concentrated in vacuo. The crude product waspurified by silica gel chromatography (0-3% methanol in methylenechloride gradient) to yield material which was subsequently trituratedwith ether to give pure2-amino-9-[2-(1H-pyrrol-1-yl)ethyl]-9H-pyrido[2,3-b]indole-3-carboxamideas a white powder (20, 25 mg, 25%). NH₄OAc standard conditions. DADRetention time=6.79 min. M+H=320. ¹H NMR (300 MHz, DMSO-d₆):

8.71 (s, 1H), 7.97-7.89 (m, 1H), 7.79-7.69 (m, 1H), 7.67-7.50 (m, 2H),7.24-7.04 (m, 4H), 6.62-6.59 (m, 2H), 5.88-5.82 (m, 2H), 4.57-4.47 (m,2H), 4.34-4.24 (m, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thesynthesis of 20.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 19 AA 340338 5.89 20 AA 320 318 6.79

2-amino-9-(2-hydroxy-2-methylpropyl)-9H-pyrido[2,3-b]indole-3-carboxamide(43)

2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 200 mg, 0.884 mmol),isobutylene oxide (0.196 mL, 2.21 mmol) and cesium carbonate (460 mg,1.40 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at 100° C.under microwave irradiation for 10 min. The volatiles were removed invacuo then the crude residue was adsorbed onto silica gel using methanoland purified by silica gel chromatography (5-10% methanol in methylenechloride gradient) to afford the title compound (43, 185 mg, 70%).NH₄OAc standard conditions. DAD Retention time=5.93 min. M+H=299. ¹H NMR(300 MHz, MeOD-d₄):

8.64 (d, J=4.9 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H),7.34 (dd, J=7.6, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 5.49 (s,2H), 1.28 (s, 6H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 43. In the case of 72, a TFA deprotection (following theprocedure outlined in the preparation of 30) was utilized to generatethe compound listed below.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 43 AA 2995.93 53 AA 311 6.19 57 AA 285 5.52 72 AA 326 324 4.43

2-amino-9-[(benzyloxy)acetyl]-9H-pyrido[2,3-b]indole-3-carboxamide (28)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 150mg, 0.663 mmol) in pyridine (7 mL) was added EDC (210 mg, 1.10 mmol),DMAP (85 mg, 0.693 mmol) and benzyloxyacetic acid (142 μL, 0.994 mmol)and the mixture was stirred at RT under an atmosphere of Ar. After 23 h,the reaction was quenched with water (20 mL), poured into a separatoryfunnel containing EtOAc (100 mL) and washed with water (75 mL). Theorganic layer was washed with brine (100 mL), dried over sodium sulfate,filtered and concentrated. The crude product was purified by HPLC(Phenomenex Luna 15 μm C18, aqueous HCOOH/CH₃CN) to yield2-amino-9-[(benzyloxy)acetyl]-9H-pyrido[2,3-b]indole-3-carboxamide (28,54 mg, 22%). NH₄OAc standard conditions. DAD Retention time=7.6 min.M+H=375. ¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.52-8.49 (m, 1H),8.04 (br s, 1H), 7.83-7.77 (m, 3H), 7.47-7.29 (m, 8H), 5.30 (s, 2H),4.72 (s, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 28.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 27 AA 384382 7.11 11 AA 346 344 6.3 28 AA 375 7.6

2-amino-9-benzoyl-9H-pyrido[2,3-b]indole-3-carboxamide (8)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 42.0mg, 0.186 mmol) in pyridine (1 mL) was added DMAP (57 mg, 0.467 mmol)and benzoyl peroxide (281 mg, 1.16 mmol). The mixture was stirred at RT.After 24 h, the reaction was concentrated, diluted with EtOAc (100 mL),poured into a separatory funnel and washed with water (2×75 mL). Theorganic layer was dried, filtered and concentrated. The crude wasdissolved in EtOAc (100 mL) and washed with saturated aqueous NaHCO₃(2×50 mL) and 1 N NaOH (50 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated to yield2-amino-9-benzoyl-9H-pyrido[2,3-b]indole-3-carboxamide as a yellow solid(8, 34 mg, 56%). HCOOH standard conditions. DAD Retention time=6.65 min.M+H=331. ¹H NMR (300 MHz, DMSO-d₆):

8.78 (s, 1H), 8.04 (br s, 1H), 7.92-7.86 (m, 2H), 7.75-7.72 (m, 2H),7.67 (d, J=7.5 Hz, 1H), 7.54-7.48 (m, 2H), 7.40-7.37 (m, 3H), 7.13 (brs, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 8.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 6 AA 269267 6.33 7 FA 297 295 6.97 8 FA 331 6.65

2-amino-9-[(dimethylamino)sulfonyl]-9H-pyrido[2,3-b]indole-3-carboxamide(17)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 138mg, 0.610 mmol) in a 1:1 mixture of THF-DMF (4.5 mL) was added NaH (73.0mg, 2.50 mmol). The mixture was stirred at RT. After 10-15 min,dimethylsulfamoyl chloride (212 mL, 1.10 mmol) was added and thereaction was stirred for another 2 h. The reaction was quenched withwater (50 mL) and poured into a separatory funnel containing EtOAc (100mL). The mixture was shaken and the layers were separated. The organiclayer was washed with brine (50 mL), dried over sodium sulfate, filteredand concentrated. The crude product was purified by HPLC (PhenomenexLuna 15 μm C18, aqueous HCOOH/CH₃CN) to give2-amino-9-[(dimethylamino)sulfonyl]-9H-pyrido[2,3-b]indole-3-carboxamideas a white powder (17, 24.9 mg, 12%). HCOOH standard conditions. DADRetention time=3.68 min. M+H=334. ¹H NMR (300 MHz, DMSO-d₆): δ 8.78 (s,1H), 8.06 (s, 1H), 8.00-7.97 (m, 1H), 7.84-7.81 (m, 1H), 7.72 (br s,2H), 7.40-7.32 (m, 3H), 3.02 (s, 6H).

Example 3 Deprotection of 9-N substituted α-carbolines

2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride (16)

Step 1: tert-butyl{2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]ethyl}carbamate(xvi-a)

tert-Butyl{2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]ethyl}carbamatewas prepared following the procedure detailed in the synthesis of 13,substituting tert-butyl 2-bromoethylcarbamate for 2-bromopropane. NH₄OAcQC conditions M+H=370. ¹H NMR (300 MHz, DMSO-d₆):

8.70 (s, 1H), 7.87 (br s, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.56 (m, 2H),7.44 (d, J=7.6 Hz, 1H), 7.29 (dd, J=7.0, 7.6 Hz, 1H), 7.15 (dd, J=7.6,7.6 Hz, 1H), 6.96 (dd, J=5.9, 5.9 Hz, 1H), 4.32-4.21 (m, 2H), 3.34-3.20(m, 2H), 1.28 (s, 9H).

Step 2: 2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride (16)

To a solution of tert-butyl{2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]ethyl}carbamate(xvi-a, 35.0 mg, 0.095 mmol) in MeOH (2 mL) was added conc. HCl (1 mL).The reaction was stirred at RT. After 2 h, the reaction was concentratedand lyophilized to yield2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride as a white solid (16, 27 mg, 93%). NH₄OAc standardconditions. DAD Retention time=4.48 min. M+H=270. ¹H NMR (300 MHz, D₂O):

8.16 (s, 1), 7.74 (d, J=7.6 Hz, 1H), 7.73-7.42 (m, 1H), 7.36-7.28 (m,2H), 4.32 (t, J=5.7 Hz, 2H), 3.37 (t, J=5.7 Hz, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 16.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 16 Aa 2704.48 15 Aa 284 282 4.68 25 Aa 284 282 5.22

2-amino-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (30)

Step 1: tert-butyl [(1S)-2-iodo-1-methylethyl]carbamate (xxvii)

PS-triphenylphosphine (2.5 mmol/g, 1.3 g, 3.3 mmol) was suspended inmethylene chloride (12 mL). Imidazole (225 mg, 3.3 mmol) was added andthe mixture was cooled to 0° C. in an ice-water bath. To the cooledmixture was added iodine (838 mg, 3.3 mmol), and the resulting mixturewas warmed to room temperature, stirred 10 minutes and recooled to 0° C.Boc-L-alaminol (463 mg, 2.64 mmol) in methylene chloride (3 mL) wasadded over several minutes. The resulting mixture was stirred at 0° C.for 1 hour, warmed to room temperature and stirred 2 h. The mixture wasfiltered. The solids collected were washed thoroughly with ethylacetate. The filtrate was washed with dilute aqueous HCl (3%), sodiumthiosulfate (1 M), saturated aqueous sodium bicarbonate and brine. Theextracts were then dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude tert-butyl[(1S)-2-iodo-1-methylethyl]carbamate (xxvii) was obtained as a yellowoil and used without further purification. ¹H NMR (300 MHz, CDCl₃): δ3.34-3.56 (m, 2H), 3.27 (dd, J=3.7, 9.8 Hz, 1H), 1.43 (s, 9H), 1.18 (d,J=6.7 Hz, 3H).

Step 2: tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xvi-b)

tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xvi-b) was prepared following the procedure detailed in the synthesisof 13 substituting tert-butyl [(1S)-2-iodo-1-methylethyl]carbamate for2-bromopropane. HCOOH Standard Conditions. M+H=384. ¹H NMR (300 MHz,d₆-DMSO): δ 8.71 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.59 (d, J=7.9 Hz,1H), 7.57-7.49 (br s, 2H), 7.31 (dd, J=7.9, 7.3 Hz, 1H), 7.16 (dd,J=7.9, 7.3 Hz, 1H), 6.90 (br d, 1H), 4.27 (dd, J=6.1, 13.4 Hz, 1H),4.14-3.95 (m, 2H), 1.18 (s, 9H), 1.05 (d, J=6.1 Hz, 3H)

Step 3:2-amino-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (30)

tert-Butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xvi-b, 400. mg, 1.04 mmol), was dissolved in methylene chloride (10 mL)to which trifluoroacetic acid (2 mL) was subsequently added. The mixturewas stirred at room temperature until consumption of starting materialwas complete. The reaction mixture was diluted with ethyl acetate (20mL) and basified by addition of 6 N aqueous sodium hydroxide solution.The extracts were washed with brine, dried over sodium sulfate, filteredand concentrated. The crude material was dissolved in minimal methanoland then acidified by the addition of HCl in ether (1 M). The pureproduct was isolated as its hydrochloride salt by filtration (196 mg,59%). NH₄OAc standard conditions. DAD Retention time=4.92 min. M+H=284.¹H NMR (300 MHz, CD₃OD): δ 8.77 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.53(d, J=8.2 Hz, 1H), 7.43 (dd, J=8.2, 7.0 Hz, 1H), 7.28 (dd, J=7.6, 7.0Hz, 1H), 4.62-4.47 (m, 2H), 4.01-3.89 (m, 1H), 1.40 (d, J=6.5 Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 30.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 30 AA 2844.92 31 AA 284 282  4.8 39 FA (QC conditions) 298 0.97 (QC conditions)41 FA 312 3.99

2-amino-9-[(2R)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (35)

Step 1: benzyl{(1R)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xxiv-a)

benzyl{(1R)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xxiv-a) was prepared following the procedure detailed in the synthesisof 13, substituting benzyl [(1R)-2-iodo-1-methylethyl]carbamate (madefrom commercial N-benzyloxycarbonyl-D-alaninol) for 2-iodopropane.

Step 2:2-amino-9-[(2R)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (35)

To a solution of benzyl{(1R)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xxiv-a, 13 mg, 0.031 mmol) in ethanol (10 mL) was added palladium oncarbon (10 mg, 0.094 mmol). The reaction mixture was stirred under ahydrogen atmosphere overnight. Solids were removed by filtration and thefiltrate was concentrated in vacuo to afford2-amino-9-[(2R)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (35,7.6 mg, 86%). NH₄OAc standard conditions. DAD Retention time=4.90 min.M+H=284. ¹H NMR (300 MHz, MeOD-d₄):

8.66 (s, 1H), 7.90 (d, J=7.7 Hz, 1H) 7.49 (d, J=8.1 Hz, 1H), 7.23 (ddd,J=7.4, 6.9, 1.2 Hz, 1H), 7.17 (ddd, J₁=7.8, 7.7, 1.2 Hz, 1H), 4.33 (d,J=6.1 Hz, 2H), 3.63-3.71 (m, 1H), 1.23 (d, J=6.5 Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 35.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 26 AA 284282 5.2 35 AA 284 4.9

2-amino-9-(2-hydroxyethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (9)

Step 1:2-amino-9-(2-(tert-butyldimethylsilyloxy)ethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(xxv-a)

2-Amino-9-(2-(tert-butyldimethylsilyloxy)ethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(xxv-a) was prepared following the procedure detailed in the synthesisof 13 substituting (2-bromoethoxy)(tert-butyl)dimethylsilane for2-bromopropane. The crude silane was used in the following step withoutfurther purification. NH₄OAc QC conditions. M+H=385.

Step 2: 2-amino-9-(2-hydroxyethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(9)

2-Amino-9-(2-(tert-butyldimethylsilyloxy)ethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(xxv-a, 360 mg, 1.06 mmol) was dissolved in tetrahydrofuran (3 mL). Asolution of tetrabutylammonium fluoride (1.0 M in THF, 1.3 mL, 1.4 mmol)was added. The resulting solution was stirred at room temperature 3 h.The solution was concentrated under reduced pressure. The residue wastriturated with methylene chloride. The resulted solids were dissolvedin tetrahydrofuran and washed with brine. The extracts were dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography (12 g silica,methylene chloride to 3% methanol in methylene chloride gradient). Theproduct 9 was isolated as a yellow solid (30 mg, 10% for 2 steps).NH₄OAc standard conditions. DAD retention time=5.02 min. M+H=271. ¹H NMR(300 MHz, DMSO-d₆):

8.66 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.59-7.50 (br s, 1H), 7.46 (d,J=8.2 Hz, 1H), 7.25 (ddd, J=1.7, 7.0, 8.2 Hz, 1H), 7.11 (dd, J=7.0, 7.0Hz, 1H), 4.30-4.23 (m, 2H), 3.72-3.66 (m, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described thepreparation of 9.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 9 AA 271269 5.02 12 AA 285 283 5.37

Example 16a2-amino-9-{2-amino-1-[(benzyloxy)methyl]ethyl}-9H-pyrido[2,3-b]indole-3-carboxamide(73)

Step 1: tert-Butyl3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate(xvi-c)

tert-Butyl3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate(xvi-c) was prepared following the procedure detailed in the synthesisof 63, substituting tert-butyl [3-(benzyloxy)-2-iodopropyl]carbamate(prepared from tert-butyl 3-(benzyloxy)-2-hydroxypropylcarbamate[Nagashima, N. Chem. Pharm. Bull. 1991, 39, 1972-1982] as detailed inthe preparation of xxvii) for tert-butyl[1-(iodomethyl)cyclopropyl]carbamate. NH₄OAc QC conditions. M+H=382tert-Butyl3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate(xvi-c) was used directly in the following deprotection step.

Step 2:2-Amino-9-{2-amino-1-[(benzyloxy)methyl]ethyl}-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride (73)

Deprotection of xvi-c following the HCl/methanol deprotection proceduredetailed in the second step of the synthesis of 16 afforded2-amino-9-{2-amino-1-[(benzyloxy)methyl]ethyl}-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride (73, 11 mg, 5%). NH₄OAc standard conditions. DAD Retentiontime=6.72 min. M+1=282. ¹H NMR (300 MHz, MeOD): δ 8.88 (s, 1H), 7.96 (d,J=7.6 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.35-7.22(m, 7H), 4.70 (d, J=6.4 Hz, 2H), 4.52-4.50 (m, 2H), 4.10-3.96 (m, 1H),3.75-3.38 (m, 1H), 3.60-3.50 (m, 1H).

2-amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamide(61)

Step 1: (R)-tert-butyl1-(2-amino-3-carbamoyl-9H-pyrido[2,3-b]indol-9-yl)-3-(benzyloxy)propan-2-ylcarbamate(xvi-d)

(R)-tert-butyl1-(2-amino-3-carbamoyl-9H-pyrido[2,3-b]indol-9-yl)-3-(benzyloxy)propan-2-ylcarbamate(xvi-d) was prepared following the procedure detailed in the preparationof 63, substituting (S)-tert-butyl1-(benzyloxy)-3-iodopropan-2-ylcarbamate (prepared as detailed in thesynthesis of xxvii from commercial N-Boc-L-Ser(Bzl)-ol) for tert-butyl[1-(iodomethyl)cyclopropyl]carbamate. NH₄OAc QC conditions. M+H=490.

Step 2:2-Amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride (61)

2-Amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamidehydrochloride (61) was obtained from xvi-d following the TFAdeprotection procedure outlined in the preparation of 30 to yield thetitled compound (61, 20 mg, 70%). NH₄OAc standard conditions. DADRetention time=6.70 min. M+H=390. ¹H NMR (300 MHz, DMSO-d₆): δ 8.78 (s,1H), 7.82 (d, J=7.3 Hz, 1H), 7.61 (d, J=7.94 Hz, 1H), 7.36-7.20 (m, 8H),4.62-4.42 (m, 2H), 4.48 (s, 2H), 3.88-3.80 (m, 1H), 3.64-3.44 (m, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thesynthesis of 61.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 61 AA 390388 6.70 64 AA 296 5.46

2-Amino-9-[(2R)-2-amino-3-hydroxypropyl]-9H-pyrido[2,3-b]indole-3-carboxamide(65)

To a cooled (0° C.) solution of2-amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamide(61, 81 mg, 0.160 mmol) in chloroform (2 mL) was addediodotrimethylsilane (140 uL, 0.990 mmol). The reaction was stirred underargon, allowed to warm slowly to room temperature and then stirred anadditional 16 h. The reaction mixture was filtered and concentrated invacuo. The crude mixture was purified by reverse phase HPLC (PhenomenexLuna 15 μm C18, aqueous NH₄OAc/CH₃CN) to provide the product which wasthen converted to the hydrochloride salt by stirring with a solution ofexcess hydrochloric acid in methanol to afford2-amino-9-[(2R)-2-amino-3-hydroxypropyl]-9H-pyrido[2,3-b]indole-3-carboxamide(65, 24 mg, 45%). NH₄OAc standard conditions. DAD Retention time=4.76min. M+H=300. ¹H NMR (300 MHz, MeOD-d₄):

8.97 (s, 1H), 8.01 (d, J=7.0 Hz, 1H) 7.67 (d, J=7.4 Hz, 1H), 7.52 (t,J=6.9, 1H), 7.38 (t, J=6.9 Hz, 1H), 4.75-4.69 (m, 2H), 3.96-3.81 (m,2H), 3.71-3.62 (m, 1H).

2-amino-9-(pyrrolidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(40)

Step 1: tert-butyl2-{[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-methyl}pyrrolidine-1-carboxylate(xvi-e)

To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 50 mg,0.2 mmol) in N,N-dimethylformamide (0.5 mL) was added powdered sodiumhydroxide (12 mg, 0.31 mmol) and tetrabutylammonium hydrogen sulfate (3mg, 0.009 mmol). The mixture was stirred at room temperature for 30 minthen tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate (67 mg, 0.25mmol) was added. The resulting mixture was stirred at room temperaturefor 4 days. Water (5 ml) was added to the mixture, followed by HCl (3%aqueous, 1 mL). The mixture was extracted with ethyl acetate (3×30 ml).The extracts were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (12 g silica, methylene chloride to 90/10methylene chloride/methanol gradient) to yield tert-butyl2-{[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]methyl}pyrrolidine-1-carboxylate(xvi-e, 20 mg, 20%). NH₄OAc QC conditions. M+1=410.

Step 2:2-amino-9-(pyrrolidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide

2-Amino-9-(pyrrolidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(40) was obtained following the TFA deprotection of xvi-e as detailed inthe preparation of 30 to yield the title compound (40, 18 mg, 70%).NH₄OAc standard conditions. DAD Retention time=5.13 min. M+H=310. ¹H NMR(300 MHz, MeOD): δ 8.82 (s, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.61 (d, J=7.3Hz, 1H), 7.45 (t, J=6.9 Hz, 1H), 7.31 (t, J=6.9 Hz, 1H), 4.78-4.70 (m,2H), 4.20-4.05 (m, 1H), 3.55-3.44 (m, 1H), 2.37-2.22 (m, 1H), 2.12-1.97(m, 3H), 1.93-1.78 (m, 1H).

2-amino-9-azetidin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (50)

Step 1: tert-butyl3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate(xvi-f)

To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide(5, 44 mg, 0.19 mmol) in N,N-dimethylformamide (4.4 mL) was addedpowdered cesium carbonate (130 mg, 0.39 mmol), and tert-butyl3-iodoazetidine-1-carboxylate (Harris, L. J., et al. European PatentApplication 1176142, 2002; 0.11 g, 0.39 mmol). The mixture was heated ina microwave at 150° C. for 30 min, concentrated and purified by silicagel chromatography (12 g silica, methylene chloride to 90/10 methylenechloride/methanol gradient) to yield tert-butyl3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate(xvi-f, 50 mg, 70%). NH₄OAc QC conditions. M+H=382. ¹H NMR (300 MHz,CDCl₃): δ 8.24 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H),7.42-7.34 (m, 1H), 7.30-7.22 (m, 1H), 4.75-4.60 (m, 1H), 4.48-4.39 (m,2H), 4.17-4.07 (m, 2H), 1.51 (s, 9H).

Step 2: 2-amino-9-azetidin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide(50)

2-Amino-9-azetidin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (50) wasmade following the trifluoroacetic acid deprotection procedure detailedin the preparation of 30 affording the titled compound (50, 20 mg, 40%).NH₄OAc standard conditions. DAD Retention time=4.97 min. M+H=282. ¹H NMR(300 MHz, MeOD): δ 8.72 (s, 1H), 7.90 (d, J=6.9 Hz, 1H), 7.48-7.30 (m,2H), 7.27-7.22 (m, 1H), 4.78-4.50 (m, 1H), 4.30-4.20 (m, 2H), 3.85-4.00(m, 2H).

Compounds in the following table were prepared from the appropriatestarting materials (mesylate or iodide) in a method analogous to thatdescribed in the preparation of 50.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 52 AA 298296 5.28 50 AA 282 4.97

2-amino-9-{2-[(chloroacetyl)amino]-2-methylpropyl}-9H-pyrido[2,3-b]indole-3-carboxamide(56)

Concentrated sulfuric acid (1.0 mL) was added dropwise to a solution of43 (120 mg, 0.102 mmol) in chloroacetonitrile (1.0 mL) at 0° C. Stirringcontinued at this temperature for 1 h, then the reaction was dilutedwith water (5 mL) and the pH adjusted to 8-9 with 1N sodium hydroxidethen aqueous saturated sodium bicarbonate. The aqueous phase wasextracted with ethyl acetate (50 mL×3) then the combined organic phaseswere dried over sodium sulfate and concentrated in vacuo. The residuewas purified by silica gel chromatography (5-10% methanol in methylenechloride gradient) to afford the title compound (56, 120 mg, 80%).NH₄OAc standard conditions. DAD Retention time=6.59 min. M+H=374. ¹H NMR(300 MHz, CDCl₃):

8.39 (br s, 1H), 8.27 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.36-7.34 (m,2H), 7.22 (dd, J=7.3, 7.3 Hz, 1H), 6.83 (br s, 2H), 5.80 (br s, 2H),4.28 (s, 2H), 3.87 (s, 2H), 1.55 (s, 6H).

2-amino-9-{2-[(chloroacetyl)amino]-2-methylpropyl}-9H-pyrido[2,3-b]indole-3-carboxamide(47)

A solution of 56 (50 mg, 0.134 mmol) and thiourea (21 mg, 0.28 mmol) inethanol (1.0 mL) was stirred under microwave irradiation for 15 min at150° C. After cooling to room temperature the reaction was diluted withsaturated aqueous sodium bicarbonate solution (10 mL) and extracted withethyl acetate (3×20 mL). The combined organic phases were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo toafford the title compound (47, 24 mg, 60%). NH₄OAc standard conditions.DAD Retention time=5.24 min. M+H=298. ¹H NMR (300 MHz, MeOD-d₄):

8.70 (br s, 1H), 8.37 (s, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.1Hz, 1H), 7.40 (dd, J=7.7, 7.3 Hz, 1H), 7.26 (dd, J=8.1, 7.3 Hz, 1H),4.44 (s, 2H), 1.50 (s, 6H).

2-amino-9-(2-amino-2-iminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide(42)

Hydrogen chloride gas was bubbled through ice-cooled absolute ethanol(15 mL) for 5 min to prepare a saturated solution.2-Amino-9-(cyanomethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (36, 29 mg,0.107 mmol) in ethanol (1 mL) was added, the resulting solution stirredat room temperature for 90 min and then all volatiles were removed invacuo. The resulting residue was diluted with ammonia in methanol (7.0M, 10.0 mL) and stirred at room temperature for 16 h. The crude reactionmixture was concentrated in vacuo and the residue purified by reversephase C-18 silica gel chromatography [0-70% acetonitrile in water(containing 0.1% TFA)] to afford the title compound (42, 28 mg, 91%) asthe trifluoroacetate salt. NH₄OAc standard conditions. DAD Retentiontime=4.53 min. M+H=311. ¹H NMR (300 MHz, DMSO-d₆):

8.95 (br s, 1H), 8.91 (br s, 1H), 8.77 (s, 1H), 7.94 (br s, 1H), 7.83(d, J=7.3 Hz, 1H), 7.65 (br s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.35 (dd,J=7.9, 7.3 Hz, 1H), 7.26 (dd, J=7.3, 7.3 Hz, 1H), 5.22 (s, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 42.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 42 AA 2834.16 58 AA 311 4.53 59 AA 309 307 4.49

Example 4 Synthesis of compounds where R³ is T₁-R^(3d) or —V₁-T₁-R^(3d)and T₁ is substituted with —NR′C(O)R^(3a) or NC(═N)NH₂

9-[2-(acetylamino)ethyl]-2-amino-9H-pyrido[2,3-b]indole-3-carboxamide(22)

To a solution of2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (16, 50.0mg, 0.186 mmol) in pyridine (2 mL) was added DMAP (23.0 mg, 0.188 mmol)and acetic anhydride (23 μL, 0.243 mmol). The reaction was stirred at RTunder an atmosphere of argon. After 1 h, the reaction was concentratedand the crude product was purified by HPLC (Phenomenex Luna 15 μm C18,aqueous NH₄OAc/CH₃CN) to yield9-[2-(acetylamino)ethyl]-2-amino-9H-pyrido[2,3-b]indole-3-carboxamide(22, 11 mg, 19%). NH₄OAc standard conditions. DAD Retention time=5.18min. M+H=312. ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.01 (t, J=5.7Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.58 (br s, 2H), 7.46 (d, J=8.1 Hz,1H), 7.33 (t, J=8.1 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 4.31 (t, J=6.0 Hz,2H), 3.41 (q, J=6.0 Hz, 2H), 1.71 (s, 3H).

2-amino-9-((2S)-2-{[amino(imino)methyl]amino}propyl)-9H-pyrido[2,3-b]indole-3-carboxamide(71)

To a solution of2-amino-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (30,100 mg, 0.350 mmol) in methylene chloride (3 mL) was added PL-DCC resin(394 mg, 0.575 mmol) and the mixture was stirred at room temperature for15 min. N,N′-bis-tert-butoxycarbonylthiourea (112 mg, 0.406 mmol) wasadded and the reaction mixture was stirred at room temperatureovernight. PS-trisamine resin (4.12 g, 3.6 mmol/g, 14.8 mmol) wassubsequently added and the resulting mixture was stirred at roomtemperature overnight. The resins were removed by suction filtration andthe filtrate was concentrated under reduced pressure. Purification ofthe crude material by reverse phase C-18 silica gel chromatography[0-70% acetonitrile in water (containing 0.1% TFA)] afforded2-amino-9-((2S)-2-{[amino(imino)methyl]amino}propyl)-9H-pyrido[2,3-b]indole-3-carboxamide(71, 48 mg 26%). NH₄OAc standard conditions. DAD Retention time=4.98min. M+H=326.

Example 5 Synthesis of 2-amino-substituted compounds (R¹=R^(1a),—C(O)R^(1a), —C(O)N(R^(1a))₂)

2-[(aminocarbonyl)amino]-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide(21)

A solution of 2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1,71 mg, 0.28 mmol) in DCM (1 mL) was cooled to 0° C. and chlorosulfonylisocyanate (27 μL, 0.31 mmol) was added. The mixture was stirred at 0°C. under an atmosphere of argon. After 2 h, the reaction was quenchedwith a few drops of water and concentrated under reduced pressure. Thecrude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueousNH₄OAc/CH₃CN) to yield2-[(aminocarbonyl)amino]-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide(21, 15 mg, 18%). NH₄OAc standard conditions. DAD Retention time=6.40min. M+H=298. ¹H NMR (300 MHz, DMSO-d₆): δ 11.44 (s, 1H), 9.04 (s, 1H),8.70 (br s, 1H), 8.30 (br s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.1Hz, 2H), 7.49 (t, J=8.1 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (br s,1H), 4.42 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).

2-(acetylamino)-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide(66)

Step 1: tert-butyl{(1S)-2-[2-(acetylamino)-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1methylethyl}carbamate (xxxi-a)

Acetic anhydride (32.8 mL, 347 mmol) was added to a solution of2-(acetylamino)-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide(xvi-b, 442 mg, 1.15 mmol) in methylene chloride (2.0 mL). The solutionwas stirred at room temperature for 16 h then diluted with ethyl acetate(100 mL) and washed with aqueous saturated sodium bicarbonate (50 mL)and brine (50 mL). The organic phase was dried over sodium sulfate andconcentrated in vacuo to afford tert-butyl{(1S)-2-[2-(acetylamino)-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1methylethyl}carbamate (xxxi-a, 152 mg, 31%) which was used withoutfurther purification. NH₄OAc QC conditions. M+H=426.

Step 2:2-(acetylamino)-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide(66)

xxxi-a (44 mg, 0.104 mmol) was deprotected using the TFA conditionsdetailed in the preparation of 30 to afford the title compound (66, 29mg, 63%). NH₄OAc standard conditions. DAD Retention time=4.98 min.M+H=326. ¹H NMR (300 MHz, DMSO-d₆): δ 12.27 (br s, 1H), 9.05 (br s, 1H),8.41 (br s, 1H), 8.31 (br s, 3H), 8.03 (d, J=7.6 Hz, 1H), 7.80 (br s,1H), 7.75 (d, J=8.2 Hz, 1H), 7.51 (dd, J=7.6, 7.6 Hz, 1H), 7.32 (dd,J=7.0, 7.0 Hz, 1H), 4.53 (br s, 2H), 3.87-3.75 (br m, 1H), 2.32 (s, 3H),1.16 (d, J=6.5 Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 44. Step 2 may be omitted for compounds lackingalkylamine substitutents.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 49 AA 2976.43 66 AA 326 4.98

9-ethyl-2-(methylamino)-9H-pyrido[2,3-b]indole-3-carboxamide (48)

2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1, 36 mg, 0.141mmol), formaldehyde (37 wt % in water, 0.011 mL, 0.155 mmol) and aceticacid (0.0084 mL, 0.148 mmol) in methanol (2.6 mL) were stirred at roomtemperature for 1 h then sodium cyanoborohydride (13 mg, 0.212 mmol) wasadded. The reaction stirred at room temperature for 16 h, then wasquenched with aqueous saturated sodium bicarbonate (2.6 mL). Theresulting mixture was diluted with ethyl acetate (100 mL), washed withwater (2×50 mL) and brine (50 mL), dried over magnesium sulfate,filtered and then concentrated in vacuo. The residue was adsorbed ontosilica gel using methanol and purified by silica gel chromatography(5-10% methanol in methylene chloride gradient) to afford the titlecompound (48, 25 mg, 66%). NH₄OAc standard conditions. DAD Retentiontime=7.84 min. M+H=269. ¹H NMR (300 MHz, CDCl₃): δ 8.60 (br s, 1H), 8.19(s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.36-7.32 (m, 2H), 7.21-7.17 (m, 1H),5.65 (br s, 2H), 4.38 (q, J=7.3 Hz, 2H), 3.12 (s, 3H), 1.42 (t, J=7.3Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described in thepreparation of 48.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 48 AA 2697.84 69 AA 398 8.3

9-[(2S)-2-aminopropyl]-2-(methylamino)-9H-pyrido[2,3-b]indole-3-carboxamide(45)

Step 1: tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xxxii-a)

tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xvi-b, 20 mg, 0.052 mmol) was alkylated according to procedure detailedin the preparation of 48, to afford tert-butyl{(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate(xxxii-a, 20 mg, 89%). NH₄OAc QC conditions. M+H=398.

Step 2:9-[(2S)-2-aminopropyl]-2-(methylamino)-9H-pyrido[2,3-b]indole-3-carboxamide(45)

tert-butyl{(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamatexxxii-a (20 mg, 0.051 mmol) was deprotected according to the TFAprocedure detailed in the preparation of 30 to afford the title compoundas the trifluoroacetate salt (45, 7 mg, 35%). NH₄OAc standardconditions. DAD Retention time=5.33 min. M+H=298. ¹H NMR (300 MHz,CDCl₃): δ 9.04 (br s, 1H), 8.76 (s, 1H), 8.02 (br s, 4H), 7.82 (d, J=7.9Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.35 (br dd, J=7.3, 7.3 Hz, 1H), 7.23(br dd, J=7.3, 7.3 Hz, 1H), 4.48-4.44 (m, 1H), 3.04 (s, 3H), 3.57-3.52(m, 2H), 1.21 (d, J=6.1 Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that described for thesynthesis of 45.

LCMS Standard Retention No. Method: (FA/AA) ES+ ES− Time (min) 45 AA 2985.33 51 AA 312 5.79 54 AA 374 6.64 60 AA 326 324 6.22 70 AA 298 5.92

Biological Testing

Compounds of this invention are effective inhibitors of IκB kinase(IKK), and therefore, are useful for treating conditions caused oraggravated by the activity of this kinase. The in vitro and in vivo IκBkinase inhibitory activities of the compounds of formula I may bedetermined by various procedures known in the art. The potent affinitiesfor IκB kinase exhibited by the inventive compounds can be measured asan IC₅₀ value (in nM), which is the concentration (in nM) of compoundrequired to provide 50% inhibition of IκB kinase.

Following are examples of assays that can be useful for evaluating andselecting a compound that modulates IKK.

Assay for Measuring IκB Kinase Enzyme Inhibition

An in vitro assay for detecting and measuring inhibition activityagainst IκB kinase complex by candidate pharmacological agents canemploy a biotinylated GST fusion protein spanning residues 5-55 of IκBα(SwissProt Accession No. P25963, Swiss Institute of Bioinformatics,Geneva, Switzerland) and an agent for detection of the phosphorylatedproduct, e.g. a specific antibody binding only to the phosphorylatedform GS, being either monoclonal or polyclonal (e.g.,commercially-available anti-phospho-serine³² IκB antibodies). In theexample of detecting the phosphorylated product by ananti-phosphoserines^(32 and 36) IκB antibody, once theantibody-phospho-GST-IκBα complex is formed, the complex can be detectedby a variety of analytical methods (e.g., radioactivity, luminescence,fluorescence, or optical absorbance). For the use of the time resolvedfluorescence method the antibody is labeled with europium chelate andthe antibody-phospho-GST-IκBα complex is bound to biotin binding proteinconjugated to a fluorescence acceptor (e.g., Steptavidin Alexa647,Invitrogen, Carlsbad, Calif.). How to prepare materials for and conductthis assay are described in more detail below.

Isolation of the IκB Kinase Complex

An IκB-α kinase complex is prepared by first diluting 10 ml of HeLa S3cell-extracts 5100 fraction (Lee et al. (1997) Cell 88:213-222) with 40ml of 50 mM HEPES pH 7.5. Then, 40% ammonium sulfate is added andincubated on ice for 30 minutes. The resulting precipitated pellet isredissolved with 5 ml of SEC buffer (50 mM HEPES pH 7.5, 1 mM DTT, 0.5mM EDTA, 10 mM 2-glycerophosphate), clarified by centrifugation at20,000×g for 15 mM., and filtrated through a 0.22 μm filter unit. Thesample is loaded onto a 320 ml SUPEROSE-6 gel filtration FPLC column(Amersham Biosciences AB, Uppsala, Sweden) equilibrated with a SECbuffer operated at 2 ml/min flow rate at 4° C. Fractions spanning the670-kDa molecular-weight marker are pooled for activation. Akinase-containing pool is then activated by incubation with 100 nMMEKK1Δ (Lee et al. (1997) Cell 88:213-222), 250 μM MgATP, 10 mM MgCl₂, 5mM DTT, 10 mM 2-glycerophosphate, 2.5 μM Microcystin-LR, for 45 minutesat 37° C. The activated enzyme is stored at −80° C. until further use.

Measurement of IκB Kinase Phospho-Transferase Activity

To each well of a 384 well plate, compounds of various concentrations in1 μL if DMSO are incubated for 2 hours with 30 μL of assay buffer (50 mMHepes pH 7.5, 5 mM DTT, 10 mM MgCl₂ 10 mM 2-glycerophosphate, 0.1%Bovine Serum Albumin) containing a 1:90 dilution of activated enzyme,100 nM biotinylated-GST-IκBα 5-55, and 50 μM ATP. Reactions are quenchedwith the addition of 10 μL of 250 mM EDTA before the addition of 40 μLof detection buffer (50 mM Hepes pH 7.5, 0.1% Bovine Serum Albumin,0.01% Tween20, Pierce, Rockford, Ill.) containing 2 nM europium labeledanti-IκBα phosphoserine^(32 and 36) and 0.003 mg/mL StreptavidinAlexa647. Samples are allowed to incubate for 1 hour prior to reading ona Wallac Victor plate reader (Perkin Elmer Life and Analytical Sciences,Boston, Mass.). As the assay has been previously shown to be linear withrespect to enzyme concentration and time at the enzyme dilution tested,levels of time resolved fluorescence energy transfer are used todetermine the inhibition activity of candidate pharmacological agents.

The compounds of the invention are inhibitors of the IKK complex. Itwill be appreciated that compounds of this invention can exhibit IκBkinase inhibitor activities of varying degrees. Following assayprocedures described herein, the IκB kinase inhibition average IC₅₀values for the inventive compounds were generally below about 10micromolar, preferably below about 1.0 micromolar, and more preferablybelow about 100 nanomolar.

Cellular Assays: A variety of cellular assays are also useful forevaluating compounds of the invention:

Multiple Myeloma (MM) Cell Lines and Patient-Derived MM Cells Isolation

RPMI 8226 and U266 human MM cells are obtained from American TypeCulture Collection (Manassas, Va.). All MM cell lines are cultured inRPMI-1640 containing 10% fetal bovine serum (FBS, Sigma-Aldrich Co., St.Louis, Mo.), 2 mM L-glutamine, 100 U/mL penicillin (Pen) and 100 μg/mLstreptomycin (Strep) (GIBCO brand cell culture products available fromInvitrogen Life Technologies, Carlsbad, Calif.). Patient-derived MMcells are purified from patient bone marrow (BM) aspirates usingROSETTESEP (B cell enrichment kit) separation system (StemCellTechnologies, Vancouver, Canada). The purity of MM cells are confirmedby flow cytometry using PE-conjugated anti-CD138 antibody (BDBiosciences, Bedford, Mass.).

Bone Marrow Stroma Cell Cultures

Bone marrow (BM) specimens are obtained from patients with MM.Mononuclear cells (MNCs) separated by Ficoll-Hipaque densitysedimentation are used to established long-term BM cultures aspreviously described (Uchiyama et al., Blood 1993, 82:3712-3720). Cellsare harvested in Hank's Buffered Saline Solution (HESS) containing 0.25%trypsin and 0.02% EDTA, washed, and collected by centrifugation.

Cell Proliferation Via Measurement of DNA-Synthesis Rate

Proliferation is measured as described (Hideshima et al., Blood 96:2943(2000)). MM cells (3×10⁴ cells/well) are incubated in 96-well cultureplates (Corning Life Sciences, Corning, N.Y.) in the presence of mediaor an IKK inhibitor of this invention for 48 h at 37° C. DNA synthesisis measured by [³H]-thymidine ([³H]-TdR, New England Nuclear division ofPerkin Elmer Life and Analytical Sciences, Boston, Mass.) incorporationinto dividing cells. Cells are pulsed with [³H]TdR (0.5 μCi/well) duringthe last 8 h of 48 h cultures. All experiments are performed intriplicate.

MTT Cell Viability Assay

The inhibitory effect of the present compounds on MM growth is assessedby measuring the reduction of yellow tetrazolium MIT(3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) bymetabolically active cells (J. Immunol. Methods 174: 311-320, 1994).Cells from 48 h cultures are pulsed with 10 μL of 5 mg/mL MTT to eachwell for the last 4 h of the 48 h cultures, followed by 100 μLisopropanol containing 0.04N HCl. Absorbance is measured at 570 nm usinga spectrophotometer (Molecular Devices Corp., Sunnyvale Calif.).

NF-κB Activation Via Electrophoretic Mobility Shift Assay

Electrophoretic mobility shift analyses (EMSA) are carried out asdescribed (Hideshima et al., Oncogene 2001, 20:4519). Briefly, MM cellsare pre-incubated with an IKK inhibitor of this invention (10 μM for 90min) before stimulation with TNF-α (5 ng/mL) for 10 to 20 min. Cells arethen pelleted, resuspended in 400 μL of hypotonic lysis buffer (20 mMHEPES, pH 7.9, 10 mM KCl, 1 mM EDTA, 0.2% Triton X-100, 1 mM Na₃VO₄, 5mM NaF, 1 mM PMSF, 5 μg/mL leupeptin, 5 μg/mL aprotinin), and kept onice for 20 min. After centrifugation (14000 g for 5 min) at 4° C., thenuclear pellet is extracted with 100 μL hypertonic lysis buffer (20 mMHEPES, pH 7.9, 400 mM NaCl, 1 mM EDTA, 1 mM Na₃VO₄, 5 mM NaF, 1 mM PMSF,5 μg/mL leupeptin, 5 μg/mL aprotinin) on ice for 20 min. Aftercentrifugation (14000 g for 5 min) at 4° C., the supernatant iscollected as nuclear extract. Double-stranded NF-κB consensusoligonucleotide probe (5′-GGGGACTTTCCC-3′, Santa Cruz BiotechnologyInc., Santa Cruz Calif.) is end-labeled with [(³²P]ATP (50 μCi at 222TBq/mM; New England Nuclear division of Perkin Elmer Life and AnalyticalSciences, Boston, Mass.). Binding reactions containing 1 ng ofoligonucleotide and 5 μg of nuclear protein are conducted at roomtemperature for 20 min in a total volume of 10 μL of binding buffer (10mM Tris-HCl, pH 7.5, 50 mM NaCl, 1 mM MgCl₂, 0.5 mM EDTA, 0.5 mM DTT, 4%glycerol (v/v), and 0.5 μg poly (dI-dC) (Amersham Biosciences AB,Uppsala, Sweden). For supershift analysis, 1 μg of anti-p65 NF-κB Ab isadded 5 min before the reaction mixtures, immediately after addition ofradiolabeled probe. The samples are loaded onto a 4% polyacrylamide gel,transferred to Whatman paper (Whatman International, Maidstone, U.K.),and visualized by autoradiography.

Diffuse Large B-Cell Lymphoma (DLBCL) Cell Proliferation Assay

ABC-like (LY3 and Ly10) and GCB-like (Ly7 and Ly19) DLBCL cell lines(Alizadeh et al (2000) Nature 403:503-511; Davis et al. (2001) J. Exp.Med. 194:1861-1874) are maintained in growth medium (GM, Iscove'sDMEM+10% FBS) by passaging cells twice per week. Cells are starvedovernight in Iscove's DMEM medium+0.5% FBS overnight before plated inproliferation assay. On the day of the assay, cells are counted andviability is checked using Trypan Blue staining. For the Ly3 and Ly10cells, 5000 cell are plated in GM per well in a 96-well plate. The Ly7and Ly19 cells are plated at 10,000 cells per well. IKK inhibitors arefirst dissolved in DMSO and then diluted in GM to reach the finalconcentrations of 80 μM-0.01 μM. Each concentration is plated intriplicate. Cell viability is determined using a standard WST-1 cellviability assay (Roche Applied Science, Indianapolis, Ind.).

Human Peripheral Blood Monocyte (PBMC) Cytokine Release Assay

Human PBMC is purified from normal donor whole blood by Ficoll gradientmethod. After a PBS wash, PBMC are re-suspended in AIM-V medium.Serially diluted IKK inhibitors of this invention in 100% DMSO are addedat 1 μl to the bottom of a 96-well plate and mixed with 180 μl 4.5×10⁵PBMC in AIM-V media per well. After preincubating PBMC with inhibitor at37° C. for 40 min, cells are stimulated with 20 μl of either with LPS(100 ng/ml) or with anti-CD3 (0.25 μg/ml) and anti-CD28 (0.25 μg/ml)(Pharmingen division of BD Biosciences, Bedford, Mass.) at 37° C. for 5hours. The supernatants are collected and assessed for IL-1β or TN{tildeover (F)}α release using standard commercially available ELISA kits.

Human Chondrocyte Matrix Metalloproteases (MMPs) Release Assay

Human chondrocyte cell line SW1353 (ATCC, Manassas, Va.) is culturedcontaining 10% fetal bovine serum (Hyclone, Logan, Utah), 2 mML-glutamine (GIBCO brand cell culture products available from InvitrogenLife Technologies, Carlsbad, Calif.) and 1% Pen/Strep (GIBCO). Cells areseeded in 96-well Poly-D-Lysine plate (BD BIOCOAT, Black/Clear bottom,BD Biosciences, Bedford, Mass.). Serially diluted IKK inhibitors at 1 μlare added to each well of 96-well plates and mixed with 180 μl 4.5×10⁵chondrocytes per well. After pre-incubating cells with compounds for 1hr at 37° C., cells are stimulated with 20 μl IL-1β (10 ng/mL, R&DSystems Inc.) at 37° C. for 24 hrs. The supernatants are then collectedand assessed for production of matrix metalloproteinases (MMPs) usingcommercially available ELISA kits.

Human Fibroblast Like Synoviocyte (HFLS) Assay

HFLS isolated from RA synovial tissues obtained at joint replacementsurgery are provided by Cell Applications Inc. (San Diego, Calif.). IKKinhibitors of the invention are tested for their ability to block theTNF- or IL-1β-induced release of IL-6 or IL-8 from these cells usingcommercially available ELISA kits. Cell culture conditions and assaymethods are described in Aupperle et al., Journal of Immunology,163:427-433 (1999).

Human Cord Blood Derived Mast Cell Assay

Human cord blood is obtained from Cambrex (Walkersville, Md.). Mastcells are differentiated and cultured in a manner similar to thatdescribed by Hsieh et al., J. Exp. Med., 193:123-133 (2001). IKKinhibitors of the invention are tested for their ability to block theIgE- or LPS-induced TNFα release using commercially available ELISAkits.

Osteoclast Differentiation and Functional Assays

Human osteoclast precursors are obtained as cryopreserved form fromCambrex (Walkersville, Md.). The cells are differentiated in culturebased on instructions from the manufacturer. IKK inhibitors of theinvention are tested for their ability to block the differentiation,bone resorption and collagen degradation as described previously (seeKhapli, S. M., Journal of Immunol, 171:142-151 (2003); Karsdal, M. A., JBiol Chem, 278:44975-44987 (2003); and Takami, M., Journal of Immunol,169:1516-1523 (2002)).

Rat Models for Rheumatoid Arthritis

Such testing is known in the literature and include a standard rat LPSmodel as described in Conway et al., “Inhibition of Tumor NecrosisFactor-α (TNF-α) Production and Arthritis in the Rat by GW3333, a DualInhibitor of TNF—Converting Enzyme and Matrix Metalloproteinases”, J.Pharmacol. Exp. Ther. 298(3), 900-908 (2001); a rat adjuvant inducedarthritis model as described in Pharmacological Methods in the Controlof Inflammation (1989) p 363-380 “Rat Adjuvant Arthritis: A Model ofChronic Inflammation” Barry M. Weichman author of book chapter {Alan R.Liss Inc Publisher}; and a rat collagen induced arthritis model asdescribed in Pharmacological Methods in the Control of Inflammation(1989) p 395-413 “Type II Collagen Induced Arthritis in the Rat” DETrentham and RA Dynesuis-Trentham authors of book chapter {Alan R. LissInc Publisher}. See also, “Animal Models of Arthritis: Relevance toHuman Disease” (1999) by A. Bendele, J. McComb, T. Gould, T. McAbee, G.Sennello, E. Chlipala and M. Guy. Toxicologic Pathology Vol 27 (1)134-142.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments, which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments, which have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof wherein, R¹ is hydrogen,C₁-C₄aliphatic, —C(O)N(R^(1a))₂, —C(O)R^(1b), or —(CH₂)_(n)R^(1c),wherein each occurrence of R^(1a) is independently hydrogen,C(O)OR^(1d), or an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, orwherein two occurrences of R^(1a) are taken together with a nitrogenatom to which they are bound to form an optionally substituted3-7-membered heterocyclyl ring; R^(1b) is an optionally substitutedgroup selected from C₁-C₆aliphatic or phenyl; R^(1c) is —N(R^(1a))₂, oran optionally substituted phenyl or pyridyl group; R^(1d) isC₁-C₆aliphatic; and n is 1, 2 or 3; R² is hydrogen or C₁-C₄aliphatic; R³is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or R^(3e), wherein V₁ is—C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—; T₁ is a C₁-C₆alkylenechain optionally substituted with one or more independent occurrences of—R^(3b), wherein the alkylene chain optionally is interrupted by—C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₁ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; each occurrence of R^(3a) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring; eachoccurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂₉═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(3e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and each R′ is independently hydrogen or optionallysubstituted C₁₋₆aliphatic; x is 0-4; each occurrence of R⁴ isindependently-R^(4a), -T₂-R^(4d), or —V₂-T₂-R^(4d), wherein: eachoccurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R⁴¹)₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and R⁵ is —NR⁶R⁷ or —OH, wherein: R⁶ and R⁷ are each independentlyhydrogen or C₁-C₄aliphatic; provided that the compound of formula I isother than: a) 2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide; b)2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the monohydrochloridethereof, c) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxylic acid; or d)2-amino-9-(2,6-dichlorophenyl)-9H-Pyrido[2,3-b]indole-3-carboxamide. 2.A compound of formula I-A:

or a pharmaceutically acceptable salt thereof wherein, R¹ is hydrogen,C₁-C₄aliphatic, or —C(O)N(R^(1a))₂; wherein each occurrence of R^(1a) isindependently hydrogen or C₁-C₄aliphatic; R² is hydrogen orC₁-C₄aliphatic; R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or—R^(3e), wherein V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or—S(O)₂NR^(3a)—; T₁ is a C₁-C₆alkylene chain optionally substituted withone or more independent occurrences of —R^(3b), wherein the alkylenechain optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring; each occurrence of R^(3a) isindependently hydrogen or an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, orwherein two occurrences of R^(3a) are taken together with a nitrogenatom to which they are bound to form an optionally substituted3-7-membered heterocyclyl ring; each occurrence of R^(3b) isindependently halogen, —CN, —NO₂, —R^(3c), —N(R^(3a))₂, —OR^(3a),—SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂,—S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c),—N(R′)C(O)OR^(3a), —N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or twooccurrences of R^(3a) or R^(3c) are optionally taken together with theirintervening atom(s) to form an optionally substituted fused ringselected from a 6-membered aryl, or a 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(3d) is independently hydrogenor an optionally substituted group selected from 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(3e) isindependently an optionally substituted group selected from3-10-membered cycloaliphatic, or 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andeach R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic; x is 0-4; each occurrence of R⁴ is independently —R^(4a),-T₂-R^(4d), or —V₂-T₂-R^(4d), wherein: each occurrence of R^(4a) isindependently halogen, —CN, —NO₂, —R^(4c), —N(R^(4b))₂, —OR^(4b),—SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b), —C(O)OR^(4b), —C(O)N(R^(4b))₂,—S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂, —N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c),—N(R′)C(O)OR^(4b), —N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or twooccurrences of R^(4b) or R^(4c) are optionally taken together with theirintervening atom(s) to form an optionally substituted fused ringselected from a 6-membered aryl, or a 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(4b), taken together with a nitrogen atom to whichthey are bound, form an optionally substituted 3-7-membered heterocyclylring having 0-3 additional heteroatoms selected from nitrogen, oxygen,or sulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic;provided that the compound of formula I is other than: a)2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide; or b)2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the monohydrochloridethereof.
 3. The compound of claim 2, having the structure of formulaI-B:


4. The compound of claim 2, wherein R³ is -T₁-R^(3d), —V₁-T₁-R^(3d), or—R^(3e).
 5. The compound of claim 4, wherein T₁ is a C₁-C₄alkylene chainwherein the alkylene chain is optionally substituted by 1 or 2independent occurrences of R^(3b), and the alkylene chain is optionallyinterrupted by —C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—,—C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—,—N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O—, and wherein each occurrence of R^(3b) is independentlyC₁-C₃aliphatic, —CN, —N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c),—C(O)R^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂.
 6. The compound of claim5, wherein T₁ is a C₁-C₄alkylene chain wherein the alkylene chain isoptionally substituted by 1 or 2 independent occurrences of R^(3b), andthe alkylene chain is optionally interrupted by —C(R′)═C(R′)—, —N(R′)—,—O—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—,—N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—, and wherein eachoccurrence of —R^(3b) is independently C₁-C₃aliphatic, —N(R^(3a))₂,—OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂.
 7. The compound of claim 5or 6, wherein R^(3d) is hydrogen.
 8. The compound of claim 6, whereineach occurrence of R^(3b) is independently —N(R^(3a))₂, C₁-C₃alkyl,—OR^(3a).
 9. The compound of claim 2, wherein x is 0, 1, or 2, and eachoccurrence of R⁴ is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —S(O)₂R^(4c), —C(O)R^(4b), —C(O)OR^(4b),—C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or —N(R′)SO₂R^(4c).10. The compound of claim 9, wherein each occurrence of R⁴ isindependently halogen, —R^(4c), —N(R^(4b))₂, —OR^(4b), or —SR^(4c). 11.The compound of claim 10, wherein each occurrence of R⁴ is independentlyhalogen or C₁-C₄alkyl.
 12. The compound of claim 2, having the structureof formula I-B:

wherein R³ is -T₁-R^(3d), T₁ is a C₁-C₄alkylene chain wherein thealkylene chain is optionally substituted by 1 or 2 independentoccurrences of R^(3b), and the alkylene chain is optionally interruptedby —C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; R^(ad) ishydrogen; each occurrence of R^(3b) is independently C₁-C₃aliphatic,—N(R^(3a))₂, —OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3e), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂; x is 0, 1, or 2; and eachoccurrence of R⁴ is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —N(R′)C(O)R⁴¹, or—N(R′)SO₂R^(4c).
 13. The compound of claim 12, wherein T₁ is C₁-C₄alkylsubstituted with 1 or 2 independent occurrences of —R^(3b), wherein eachoccurrence of —R^(3b) is independently —N(R^(3a))₂, —OR^(3a), orC₁-C₃alkyl.
 14. The compound of claim 1, wherein the compound isselected from:


15. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 16. A method of treating cancer ina patient comprising administering to said patient a therapeuticallyeffective amount of a compound of claim
 1. 17. The method of claim 16wherein the cancer is lymphoma, multiple myeloma, osteolytic bonemetastasis, head or neck cancer, lung cancer, prostate cancer, orpancreatic cancer.
 18. The method of claim 17 wherein the cancer isNon-Hodgkin's lymphoma, multiple myeloma, or head and neck squamous cellcarcinoma.
 19. A method of treating an inflammatory disease orimmune-related disease in a patient comprising administering to saidpatient a therapeutically effective amount of a compound of claim
 1. 20.The method of claim 18 wherein the disease is rheumatoid arthritis,asthma, psoriasis, psoriatic arthritis, chronic obstructive pulmonarydisease, inflammatory bowel disease, or multiple sclerosis.
 21. Themethod of claim 20, wherein the disease is rheumatoid arthritis,multiple sclerosis, asthma, or chronic obstructive pulmonary disease.22. A method of inhibiting IKK in a patient comprising administering tosaid patient a compound of claim
 1. 23. A method of inhibiting IKK in abiological sample comprising contacting said sample with a compound ofclaim
 1. 24. An intermediate of formula II:

wherein: R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e),wherein V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—; T₁ is aC₁-C₆alkylene chain optionally substituted with one or more independentoccurrences of —R^(3b), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₁ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; each occurrence of R^(3a) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring; eachoccurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(3e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and each R′ is independently hydrogen or optionallysubstituted C₁₋₆aliphatic; x is 0-4; each occurrence of R⁴ isindependently —R^(4a), -T₂-R^(4d), or —V₂-T₂-R^(4d), wherein: eachoccurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; R⁵ is —NR⁶R⁷ or —OH, wherein: R⁶ and R⁷ are each independentlyhydrogen or C₁-C₄aliphatic; and R⁸ is C₁-C₄alkyl; provided that theintermediate of formula II is other than: a)2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide, b)2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide, or c)2-cyano-3-[1-(2,6-dichlorophenyl)-2-ethoxy-1H-indol-3-yl]-2-Propenamide25. An intermediate of formula II-A:

wherein: R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e),and V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—; T₁ is aC₁-C₆alkylene chain optionally substituted with one or more independentoccurrences of —R^(3b), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₁ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; each occurrence of R^(3a) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring; eachoccurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; and each occurrence of R^(3e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,or 3-10-membered heterocyclyl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each —R′ is independentlyhydrogen or optionally substituted C₁₋₆aliphatic; x is 0-4; eachoccurrence of R⁴ is independently-R^(4a), -T₂-R^(4d), or —V₂-T₂-R^(4d),wherein: each occurrence of R^(4a) is independently halogen, —CN, —NO₂,R^(4c), —N(R^(4b))₂, —OR^(4b), —SR^(4c), S(O)₂R^(4c), —C(O)R^(4b),C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic; andR⁸ is C₁-C₄alkyl; provided that the intermediate of formula II-A isother than: a) 2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide,or b) 2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide.
 26. Theintermediate of claim 25, wherein R³ is -T₁-R^(3d), T₁ is aC₁-C₄alkylene chain wherein the alkylene chain is optionally substitutedby 1 or 2 independent occurrences of —R^(3b), and the alkylene chain isoptionally interrupted by —C(R′)═C(R′)—, —N(R′)—, —O—, —S(O)₂—, —C(O)—,—C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O—; R^(3d) is hydrogen; each occurrence of —R^(3b) isindependently C₁-C₃aliphatic, —N(R^(3a))₂, —OR^(3a), —C(O)OR^(3a),—C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a),—N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a), —N(R′)C(O)N(R^(3a))₂, or—N(R′)SO₂N(R^(3a))₂; x is 0, 1, or 2; and each occurrence of R⁴ isindependently halogen, —CN, —NO₂, —R^(4c), —N(R^(4b))₂, —OR^(4b),—SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b), —C(O)OR^(4b), —C(O)N(R^(4b))₂,—S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or —N(R′)SO₂R^(4c).
 27. The compoundof claim 26, wherein T₁ is C₁-C₄alkyl substituted with 1 or 2independent occurrences of R^(3b), wherein each occurrence of R^(3b) isindependently —N(R^(3a))₂, —OR^(3a), or —C₁-C₃alkyl.
 28. A process forthe synthesis of a compound of formula I

or a pharmaceutically acceptable salt thereof wherein, R¹ is hydrogen,C₁-C₄aliphatic, —C(O)N(R^(1a))₂, —C(O)R^(1b), or —(CH₂)_(n)R^(1c),wherein each occurrence of R^(1a) is independently hydrogen,C(O)OR^(1d), or an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, orwherein two occurrences of R^(1a) are taken together with a nitrogenatom to which they are bound to form an optionally substituted3-7-membered heterocyclyl ring; R^(1b) is an optionally substitutedgroup selected from C₁-C₆aliphatic or phenyl; R^(1c) is —N(R^(1a))₂, oran optionally substituted phenyl or pyridyl group; R^(1d) isC₁-C₆aliphatic; and n is 1, 2 or 3; R² is hydrogen or C₁-C₄aliphatic; R³is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e), wherein V₁ is—C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—; T₁ is a C₁-C₆alkylenechain optionally substituted with one or more independent occurrences of—R^(3b), wherein the alkylene chain optionally is interrupted by—C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₁ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; each occurrence of R^(3a) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring; eachoccurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(3e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and each R′ is independently hydrogen or optionallysubstituted C₁₋₆aliphatic; x is 0-4; each occurrence of R⁴ isindependently —R^(4a), -T₂-R^(4d), or —V₂-T₂-R^(4d), wherein: eachoccurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and R⁵ is —NR⁶R⁷ or —OH, wherein: R⁶ and R⁷ are each independentlyhydrogen or C₁-C₄aliphatic; provided that the compound of formula I isother than: a) 2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide; b)2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the monohydrochloridethereof, c) 2-amino-1H-Pyrido[2,3-b]indole-3-carboxylic acid; or d)2-amino-9-(2,6-dichlorophenyl)-9H-Pyrido[2,3-b]indole-3-carboxamide,wherein the process comprises contacting an intermediate of formula IIwith an amine NHR¹R² under suitable reaction conditions, wherein: R¹ ishydrogen, C₁-C₄aliphatic, —C(O)N(R^(1a))₂, —C(O)R^(1b), or—(CH₂)_(n)R^(1c), wherein each occurrence of R^(1a) is independentlyhydrogen, C(O)OR^(1d), or an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, orwherein two occurrences of R^(1a) are taken together with a nitrogenatom to which they are bound to form an optionally substituted3-7-membered heterocyclyl ring; R^(1b) is an optionally substitutedgroup selected from C₁-C₆aliphatic or phenyl; R^(1c) is —N(R^(1a))₂, oran optionally substituted phenyl or pyridyl group; R^(1d) isC₁-C₆aliphatic; and n is 1, 2, or 3; R² is hydrogen or C₁-C₄aliphatic;and the intermediate of formula II has the structure:

wherein: R³ is —H, -T₁-R^(3d), —V₁-T₁-R^(3d), or —R^(3e), wherein V₁ is—C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—; T₁ is a C₁-C₆alkylenechain optionally substituted with one or more independent occurrences of—R^(3b), wherein the alkylene chain optionally is interrupted by—C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₁ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; each occurrence of R^(3a) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring; eachoccurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3e), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, —N(R′)SO₂N(R^(3a))₂,—NR^(3a)(C═NR^(3a))N(R^(3a))₂, ═NR^(3a), ═N—N(R^(3a))₂, ═N—OR^(3a),═N—NHC(O)R^(3a), ═N—NHCO₂R^(3a), ═N—NHSO₂R^(3a), or two occurrences ofR^(3a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(3e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur and each R′ is independently hydrogen or optionallysubstituted C₁₋₆aliphatic; x is 0-4; each occurrence of R⁴ isindependently —R^(4a), -T₂-R^(4d), or —V₂-T₂-R^(4d), wherein: eachoccurrence of R^(4a) is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4e), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; R⁵ is —NR⁶R⁷ or —OH, wherein: R⁶ and R⁷ are each independentlyhydrogen or C₁-C₄aliphatic; and R⁸ is C₁-C₄alkyl; provided that theintermediate of formula II is other than: a)2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide, b)2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide, or c)2-cyano-3-[1-(2,6-dichlorophenyl)-2-ethoxy-1H-indol-3-yl]-2-Propenamide.29. A process for the synthesis of a compound of formula I-A

wherein: R¹ is hydrogen or C₁-C₄aliphatic; R² is hydrogen orC₁-C₄aliphatic; R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or—R^(3e), wherein V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or—S(O)₂NR^(3a)—; T₁ is a C₁-C₆alkylene chain optionally substituted withone or more independent occurrences of —R^(3b), wherein the alkylenechain optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—,—OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T₁ or a portionthereof optionally forms part of an optionally substituted 3-7 memberedcycloaliphatic or heterocyclyl ring; each occurrence of R^(3a) isindependently hydrogen or an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, orwherein two occurrences of R^(3a) are taken together with a nitrogenatom to which they are bound to form an optionally substituted3-7-membered heterocyclyl ring; each occurrence of —R^(3b) isindependently halogen, —CN, —NO₂, —R^(3c), —N(R^(3a))₂, —OR^(3a),—SR^(k), —S(O)₂R^(3c), —C(O)R^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂,—S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c),—N(R′)C(O)OR^(3a), —N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or twooccurrences of R^(1a) or R^(3c) are optionally taken together with theirintervening atom(s) to form an optionally substituted fused ringselected from a 6-membered aryl, or a 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3c) is independently an optionally substitutedgroup selected from C₁₋6aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(3d) is independently hydrogenor an optionally substituted group selected from 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(3e) isindependently an optionally substituted group selected from3-10-membered cycloaliphatic, or 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andeach R′ is independently hydrogen or optionally substitutedC₁₋₆aliphatic; x is 0-4; each occurrence of R⁴ is independently —R^(4a),-T₂-R^(4d), or —V₂-T₂-R^(4d), wherein: each occurrence of —R^(4a) isindependently halogen, —CN, —NO₂, —R^(4c), —N(R^(4b))₂, —OR^(4b),—SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b), —C(O)OR^(4b), —C(O)N(R⁴⁶)₂,—S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂, —N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c),—N(R′)C(O)OR^(4b), —N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or twooccurrences of R^(4b) or R^(4c) are optionally taken together with theirintervening atom(s) to form an optionally substituted fused ringselected from a 6-membered aryl, or a 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(4b), taken together with a nitrogen atom to whichthey are bound, form an optionally substituted 3-7-membered heterocyclylring having 0-3 additional heteroatoms selected from nitrogen, oxygen,or sulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected from C₁.C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring, and R⁶ and R⁷ are each independently hydrogen or C₁-C₄aliphatic;provided that the compound of formula I is other than: a)2-amino-9-ethyl-9H-Pyrido[2,3-b]indole-3-carboxamide; or b)2-amino-1H-Pyrido[2,3-b]indole-3-carboxamide, or the monohydrochloridethereof, wherein the process comprises contacting an intermediate offormula II with an amine NHR¹R² under suitable reaction conditions,wherein: R¹ is hydrogen, or C₁-C₄aliphatic, and each occurrence ofR^(1a) is independently hydrogen or C₁-C₄aliphatic; R² is hydrogen orC₁-C₄aliphatic; and the intermediate of formula II-A has the structure:

wherein: R³ is —H, -T₁-R^(3d), —V₁—R^(3a), —V₁-T₁-R^(3d), or —R^(3e),and V₁ is —C(O)—, —S(O)₂—, —C(O)NR^(3a)—, or —S(O)₂NR^(3a)—; T₁ is aC₁-C₆alkylene chain optionally substituted with one or more independentoccurrences of —R^(3b), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)S(O)₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₁ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; each occurrence of R^(3a) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or wherein two occurrences ofR^(3a) are taken together with a nitrogen atom to which they are boundto form an optionally substituted 3-7-membered heterocyclyl ring; eachoccurrence of R^(3b) is independently halogen, —CN, —NO₂, —R^(3c),—N(R^(3a))₂, —OR^(3a), —SR^(3c), —S(O)₂R^(3c), —C(O)R^(3a),—C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂, —OC(O)N(R^(3a))₂,—N(R′)C(O)R^(3a), —N(R′)SO₂R^(3e), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂, or two occurrences ofR^(1a) or R^(3c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; and each occurrence of R^(3e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,or 3-10-membered heterocyclyl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each —R′ is independentlyhydrogen or optionally substituted C₁₋₆aliphatic; x is 0-4; eachoccurrence of R⁴ is independently —R^(4a), -T₂-R^(4d), or —V₂-T₂-R^(4d),wherein: each occurrence of R^(4a) is independently halogen, —CN, —NO₂,—R^(4c), —N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —OC(O)N(R^(4b))₂,—N(R′)C(O)R^(4b), —N(R′)SO₂R^(4c), —N(R′)C(O)OR^(4b),—N(R′)C(O)N(R^(4b))₂, or —N(R′)SO₂N(R^(4b))₂, or two occurrences ofR^(4b) or R^(4c) are optionally taken together with their interveningatom(s) to form an optionally substituted fused ring selected from a6-membered aryl, or a 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or twooccurrences of R^(4b), taken together with a nitrogen atom to which theyare bound, form an optionally substituted 3-7-membered heterocyclyl ringhaving 0-3 additional heteroatoms selected from nitrogen, oxygen, orsulfur; each occurrence of R^(4b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently an optionally substituted group selected fromC₁-C₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently hydrogen or an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₂ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₂ is independently a C₁-C₆alkylene chain optionallysubstituted with R^(4a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T₂ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; R⁵ and R⁶ are each independently hydrogen or C₁-C₄aliphatic; andR⁷ is C₁-C₄alkyl; provided that the intermediate of formula II-A isother than: a) 2-cyano-3-(2-ethoxy-1-ethyl-1H-indol-3-yl)-2-Propenamide,or b) 2-cyano-3-(2-methoxy-1H-indol-3-yl)-2-Propenamide.
 30. The processof claim 29, wherein: R¹ and R² are each hydrogen; R³ is -T₁-R^(3d), T₁is a C₁-C₄alkylene chain wherein the alkylene chain is optionallysubstituted by 1 or 2 independent occurrences of —R^(3b), and thealkylene chain is optionally interrupted by —C(R′)═C(R′)—, —N(R′)—, —O—,—S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—,—N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—,—N(R′)S(O)₂N(R⁹)—, —OC(O)—, or —C(O)N(R′)—O—; R^(3d) is hydrogen; eachoccurrence of R^(3b) is independently —C₁-C₃aliphatic, —N(R^(3a))₂,—OR^(3a), —C(O)OR^(3a), —C(O)N(R^(3a))₂, —S(O)₂N(R^(3a))₂,—OC(O)N(R^(3a))₂, —N(R′)C(O)R^(3a), —N(R′)SO₂R^(3c), —N(R′)C(O)OR^(3a),—N(R′)C(O)N(R^(3a))₂, or —N(R′)SO₂N(R^(3a))₂; x is 0, 1, or 2; and eachoccurrence of R⁴ is independently halogen, —CN, —NO₂, —R^(4c),—N(R^(4b))₂, —OR^(4b), —SR^(4c), —S(O)₂R^(4c), —C(O)R^(4b),—C(O)OR^(4b), —C(O)N(R^(4b))₂, —S(O)₂N(R^(4b))₂, —N(R′)C(O)R^(4b), or—N(R′)SO₂R^(4c).
 31. The process of claim 30, wherein R⁴ is halogen or—C₁-C₃alkyl.
 32. The process of claim 30, wherein T₁ is C₁-C₄alkylsubstituted with 1 or 2 independent occurrences of —R^(3b), wherein eachoccurrence of —R^(3b) is independently —N(R^(3a))₂, —OR^(3a), or—C₁-C₃alkyl.